Regulatory Bases for Clinical Pharmacology and Biopharmaceutics Information in a New Drug Application

8/2/2019 Regulatory Bases for Clinical Pharmacology and Biopharmaceutics Information in a New Drug Application

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Regulatory Bases for Clinical Pharmacology

and Biopharmaceutics Information in a NewDrug Application

Mehul Mehta and John Hunt

Food and Drug AdministrationRockville, Maryland, U.S.A.

Within the United States, the development and marketing of products forhuman use in the diagnosis, cure, mitigation, treatment, or prevention ofdisease, or to affect the structure or function of the body are regulated bylegislation or law that has been enacted by the U.S. Congress. Theresponsibility to interpret, promulgate and enforce congressional legislation isgiven to the U.S. Food and Drug Administration (FDA) [1]. To assist incarrying out these responsibilities, the FDA implements rules or regulationsthat are published in the Federal Register (FR) then codified in the U.S. Code ofFederal Regulations (CFR). Additionally, FDA publishes guidances that arenot legally binding but are intended to provide insight and direction on how tobest satisfy legislative and regulatory requirements plus they give the mostcurrent scientific thinking within FDA. In this chapter, key drug legislation,relevant CFR regulations, FDA guidances and more recent InternationalConference on Harmonization (ICH) guidelines that impact on, or are linkedto, or provide input as to what clinical pharmacology and biopharmaceutics

Copyright 2004 by Marcel Dekker, Inc.


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information should be provided in a new drug application (NDA) to supportapproval of a pharmaceutical product are reviewed. The parties involved in theICH guidelines are regulatory authorities of Europe, Japan, and the UnitedStates, and experts from the pharmaceutical industry in the three regions.

The reader will notice, especially during the latter part of the chapter whereindividual guidances and guidelines are discussed, that there is quite a bit ofoverlap between the U.S. and the ICH documents as well as within the ICHdocuments. However, in the view of the authors, removing or minimizingthis overlap would be a disservice to these documents and so even at the riskof being repetitious, regulatory basis which support clinical pharmacologyand biopharmaceutic information from all the relevant documents ispresented.

For the purpose of this chapter, clinical pharmacology is interpreted toencompass (i) that which the body does to a drug in terms of absorption,distribution, biotransformation and excretion (i.e., its pharmacokinetics(PK) and exposure characteristics) and (ii) what the drug and/or itsmetabolite(s) do to the body in terms of mechanism(s) of action andresultant biochemical, physiological, and/or clinical effects or outcomes(i.e., its pharmacodynamics (PD) or response characteristics) whenadministered to healthy subjects and/or the target patient population(s) thatmay include special populations where dose and/or dosing regimenchanges may or may not be needed. Biopharmaceutics is interpreted toencompass the characterization of the physical and chemical properties of adrug and/or its dosage form(s) along with determining performancecharacteristics via in vitro and/or in vivo procedures or methodologies.Often clinical pharmacology and biopharmceutics information overlap.

U.S. DRUG LEGISLATION

In the U.S., the key piece of legislation or law that sets the framework toinsure that safe and effective pharmaceutical products reach and aremaintained in the marketplace is the Federal Food, Drug and Cosmetic Act(FDCA)1 [http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm] [1]. Todaysversion of the FDCA is the culmination of numerous modifications oramendments to the original legislation that was enacted in 1938 as the result

of deaths due to a sulfanilamide product that contained diethylene glycol orantifreeze in the formulation. The 1938 FDCA set a requirement that safetyneeded to be demonstrated for drugs and before a new drug could beintroduced into interstate commerce a new drug application (NDA) neededto be submitted to FDA. Drug products marketed before 1938 werehowever exempted from the FDCA (i.e., grandfather drugs).

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Clinical Pharmacology and Biopharmaceutics Information 37

Historical and more current amendments to the FDCA include theDurham-Humphrey Amendment of 1951, the Kefauver-HarrisAmendments of 1962, the Drug Listing Act of 1972, the NationalEnvironmental Policy Act of 1974, Medical Device Amendments of 1976,the Orphan Drug Act of 1983, the Drug Price Competition, and Patent TermRestoration Act of 1984 (i.e., Waxman-Hatch Amendments), the DrugExports Amendments Act of 1986, the Prescription Drug Marketing Act of1988, the Safe Medical Devices Act of 1990, the Prescription Drug User FeeAct (PDUFA) of 1992, the FDA Modernization Act (FDAMA) of 1997 andthe Best Pharmaceuticals Act for Children of 2002. Of the nine chapters inthe present FDCA, the key chapters and sections related to drugs includeand address the following.

Chapter II of FDCADefinitions (Section 201)

In this section, definitions for key terms like drug, interstate commerce,labeling, etc. are given.

Chapter III of FDCAProhibited Acts and Penalties

(Sections 301310)

Identified in these sections are different actions or scenarios that areprohibited for drug products intended for interstate commerce (e.g.,introduction of adulterated or misbranded products, etc.). Also identifiedare the legal consequences that can occur, which include criminal charges,monetary penalties and/or seizures if one is involved in actions or scenariosthat are defined as prohibited.

Chapter V of FDCADrugs and Devices (Sections 501563)

Sections 501 and 502Adulterated and Misbranded Drugs

Within Chapter V, Section 501 addresses when a drug shall be deemedadulterated. It raises the fact that regulations can be promulgated toprescribe appropriate tests or methods of assay for the determination ofstrength, quality, or purity of drugs if such tests or methods are not set forthin an official compendium (i.e., the United States Pharmacopoeia and the

Homoeopathic Pharmacopoeia of the Unites States). Section 502 addresseswhen a drug shall be deemed misbranded.

Section 505New Drugs

Of the different chapters and sections covered in the FDCA, it is Section 505of Chapter V for New Drugs which sets the overall foundation or basis for



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having pharmaceutical manufacturers or sponsors submit information toFDA before a product is allowed to market. Section 505 establishes thatbefore the introduction of any new product into interstate commerce, anapplication needs to be filed with FDA for approval. Under Sections505(b)(1), 505(b)(2), and 505(j), three types of drug applications aredescribed. It is noted that Sections 505(b)(2) and 505(j) are the result of theDrug Price Competition and Patent Term Restoration Act of 1984.Together, these two sections replaced FDAs paper NDA policy thatpermitted an applicant to rely on studies published in the scientific literatureto demonstrate safety and effectiveness of duplicates of certain post-19622

innovator or pioneer drug products.For an NDA that is covered under 505(b)(1), the application contains

full reports of clinical investigations of safety and effectiveness that areconducted by or for the applicant. For an NDA covered under 505(b)(2),one or more of the safety and effectiveness investigations used to supportthe applications approval are not conducted by or for the applicant andthe applicant has not obtained a right of reference or use from the personby or for whom the investigations are conducted. Section 505(b)(2) allowsfor the approval of products other than generic products (see below) and itpermits the use of literature or an Agency finding of safety and/or

effectiveness of a FDA-approved drug to support the approval of aproduct.

In addition to safety and efficacy information. Section 505 also indicatesthat 505(b)(1) and (2) applications need to provide(i) a list of the articlesused as components for the drug, (ii) a statement of the composition of thedrug, (iii) a description of the methods used in, and the facilities and controlsused for the manufacture, processing, and packing of the drug, (iv) samplesof the drug and the articles used as components if requested, and (v) samples

of the proposed labeling.The third type of application is a 505(j) application that is also known

as an abbreviated new drug application (ANDA). The 505(j) application isfor duplicates of already approved products, or generic products, andalthough it is beyond the scope of this chapter, it is noted that such anapplication is to contain, among other things, information to show thatthe product for approval is the same in active ingredient, dosage form,strength, route of administration, labeling and performance characteristics

(i.e., is bioequivalent) as that of a previously approved product (i.e., thereference listed drug or RLD), that is, unless a suitability petition is filed andaccepted, for example, for a different active ingredient in a combinationdrug product, or a different dosage form, strength or route of administrationthan the RLD.

If a generic product is found to be bioequivalent to the RLD and it isapproved, it will then be included in the FDA reference text entitled,



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Approved Drug Products with Therapeutic Equivalence Evaluations whichis often referred to as the Orange Book3 [http://www.fda.gov/cder/orange/default.htm] [2]. In this book, a generic product that is bioequivalent to theRLD will be assigned a code of A which means that it can be substitutedfor the RLD product or any other generic product that is approved andcoded A.

Via Section 505(i), the bases for dealing with new pharmaceuticals thatare under investigation or development prior to filing an NDA are addressed(i.e., investigational new drug (IND) applications). This section indicatesthat regulations should be promulgated to address the investigationalsituation for new drugs. It further indicates that a clinical investigation for anew drug may begin 30 days after the applicant has submitted informationabout the drug and the intended clinical investigation. The information tobe provided should include a description of the design of the clinicalinvestigation plus information to allow an assessment of safety that is toinclude adequate information on the chemistry and manufacturing of thedrug, controls available for the drug and primary data tabulations fromanimal studies or human studies. A clinical investigation may be preventedfrom being initiated during the 30-day window of time (i.e., a clinicalhold) if insufficient information is provided to allow for assessment of

safety considerations, or there are real safety concerns based on theinformation that is provided. Following the initial IND clinicalinvestigation, the FDA allows subsequent IND clinical investigations to notbe restricted to the 30-day requirement before a study can be started.However, a clinical hold can be imposed on any IND investigation before itis started or after it is initiated if there are justified safety concerns.

Section 505APediatric Studies of DrugsAs a result of the FDA Modernization Act (1997) [http://www.fda.gov/cder/fdama], the FDCA was amended to address pediatric drug studies amongother things. If it was determined (i) for 505(b)(l) applications before a newdrugs approval (i.e., before 2002), or (ii) for an already approved drug thatis identified on a list prepared by FDA, that information related to the use ofthe drug in the pediatric population may provide health benefits to thispopulation, a written request could be sent to the drug manufacturer or

sponsor to conduct a pediatric study(s). Pediatric studies may only need toinclude pharmacokinetic studies, if appropriate, as compared to the moreclassical clinical safety and efficacy studies. This assumes that (i) the diseasebeing treated or diagnosed is similar in nature between adult and pediatricpatients, (ii) there would be a similar safety profile between adult andpediatric patients, and (iii) there are similar PK (and PD relationships ifknown) between the two populations. If a study(s) is carried out as

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requested and specified by FDA, the applicant could obtain six months ofadditional marketing exclusivity for an NDA. After January 1, 2002 allnewly submitted NDAs must include pediatric information if appropriate.However, the 2002 Best Pharmaceuticals Act for Children extended the timeto allow drug sponsors to apply for six months marketing exclusivity untilOctober 2007 for both new NDAs or drugs on FDAs list for which pediatricinformation would be important to obtain.

Section 506Fast Track Products

To facilitate the development and to expedite the review of a drug productfor the treatment of a serious or life-threatening condition where theproduct demonstrates the potential to address unmet medical needs for thecondition, Section 506 addresses this situation. The fast track approval ofsuch a product can be based on the determination that the product has aneffect on a clinical endpoint or on a surrogate endpoint that is reasonablylikely to predict clinical benefit. However, the approval of a fast trackproduct may be subject to a requirement that the sponsor conductappropriate postapproval studies to validate the surrogate endpoint orotherwise confirm the effect on the clinical endpoint within a specified

time.

Section 506AManufacturing Changes

For manufacturing changes, they are addressed in Section 506A. Thissection discusses major and other manufacturing changes in a generalsense and touches upon when a supplemental application to an NDA isneeded to support a change. A manufacturing change is considered a major

change if it is determined to have substantial potential to adversely affect theidentity, strength, quality, purity, or potency of the drug as they may relateto the safety or effectiveness of the drug. Related criteria include (i) aqualitative or quantitative formulation change for the involved drug or achange in specifications in the approved application, (ii) the determinationby regulation or guidance that completion of an appropriate clinical studydemonstrating equivalence of the drug to the drug as manufactured withoutthe change is required, or (iii) a change determined by regulation or

guidance to have a substantial potential to adversely affect the safety oreffectiveness of the drug.

Sections 525 to 528Drugs for Rare Diseases or Conditions

These sections are the result of the Orphan Drug Act of 1983. ThePharmaceuticals that are covered are for diseases or conditions that are rarein the United States. A rare disease or condition is defined as any disease



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or condition that (i) affects less than 200,000 persons in the U.S. or (ii)affects more than 200,000 persons in the U.S. for which there is noreasonable expectation that the cost of developing and making the drugavailable will be recovered from U.S. sales. This section further explains thata manufacturer or sponsor needs to request that a drug be designated for arare disease or condition before the submission of an application underSection 505(b).

For a drug that is given orphan drug status, the expectations are thatsimilar clinical pharmacology and biopharmaceutics information would beprovided in an NDA as that for a drug that is not given the orphan drugstatus.

Chapter VII of FDCAFees Relating to Drugs

(Sections 735736)

This chapter and its sections are the result of the Prescription Drug User FeeAct of 1992. Under this part of the FDCA, fees are authorized and specifiedas to what is to be charged to a drug manufacturer or sponsor who submitsa human drug application via 505(b)(1) or 505(b)(2), or as a supplement tosuch an approved application. The fees are to cover the expenses that are

incurred for the review of an application. As a result of a reauthorization in1997, fees are now not to extend past October 1, 2002 unless there isanother reauthorization.

CFR REGULATIONS

As has been previously covered, FDA is given the responsibility to interpret,promulgate and enforce U.S. drug legislation, or more specifically the

FDCA. The FDCA, although being quite specific in some sections as to whatthe intent and expectations are, other sections allow for further clarificationor interpretation of the intent, expectations and/or what is needed orrequired to comply with and enforce the law. As previously noted, to assistin carrying out its responsibilities related to the FDCA, FDA will publishnotices, proposed rules, and regulations plus finalized rules and regulationsin the FR [3] followed by codification of finalized rules and regulations inthe CFR4 [4]. For the purpose of this chapter, only highlights from parts

300.50, 312, 314, and 320 of Chapter I (Food and Drug Administration,Department of Health and Human Services) of Title 21 (Food and Drugs) ofthe CFR will be covered.

For the different CFR parts, when taking into account this chaptersobjective of addressing the regulatory bases for needing clinicalpharmacology and biopharmaceutics information in a NDA, they will becovered in a sequence and cross referenced as appropriate to allow for a



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more interrelated perspective as needed. For complete content of thediscussed parts, readers are referred to the CFR.

21 CFR 320Bioavailability and BioequivalenceRequirements

Historically, part 320 that addresses bioavailability (BA) and bioequivalence(BE) requirements was the outcome of a 1974 report that was prepared bythe Drug Bioequivalence Study Panel that was convened under the U.S.Congress Office of Technology Assessment [5]. The charge to the panel wasto examine the relationships between chemical and therapeuticequivalence of drug products and to assess the capability of currenttechnologyshort of therapeutic trials in manto determine whether drugproducts with the same physical and chemical composition producecomparable therapeutic effects. In the report one conclusion was that thestandards and regulatory practices at the time did not insure bioequivalencefor drug products. The report went on to make recommendations as to whatcould be done. As a result, in 1977 FDA finalized its Bioavailability andBioequivalence Requirements via the FR which were subsequently codifiedin the CFR.

Although the impetus for the BA and BE requirements was for assuringtherapeutic equivalence among duplicate or generic products, therequirements were also crafted to establish information needs to support theapproval of NDAs for new molecular entities (NMEs) or new chemicalentities (NCEs), as well as for defined changes for already approved NDAproducts. The inclusion of requirements for NDAs was to (i) foster betterproduct quality, (ii) define or characterize what happens to a drug and itsdosage form(s) when administered, (iii) provide information to help

understand or interpret clinical safety and efficacy findings as appropriate,and (iv) provide useful information via the products labeling or packageinsert for healthcare professionals.

Under Section 320.1, definitions are provided. The term bioavailability isdefined as the rate and extent to which the active ingredient or active moietyis absorbed from a drug product and becomes available at the site of action.It further states that for drug products that are not intended to be absorbedinto the bloodstream, bioavailability may be assessed by measurements

intended to reflect that rate and extent to which the active ingredient oractive moiety becomes available at the site of action. Other terms that aredefined include bioequivalence, drug product, pharmaceutical equivalents,and pharmaceutical alternatives (see Glossary).

For part 320, key sections and subsections include the following, forwhich some are expanded upon as needed.



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320.21 Requirements for submission of in vivo bioavailabilityand bioequivalence data.

Under this section, as related to NDAs, it indicates that Any

person submitting a full new application to the FDA shall includein the application either:

1. Evidence demonstrating the in vivo bioavailability of the drugproduct that is the subject of the application; or

2. Information to permit FDA to waive the submission ofevidence demonstrating in vivo bioavailability.

This section goes on to indicate that any person submitting a

supplemental application to FDA shall include in thesupplemental application evidence demonstrating the in vivobioavailability of the product or information to permit FDA towaive the submission of evidence demonstrating in vivobioavailability for changes that include:

1. A change in the manufacturing process, including a change inproduct formulation or dosage strength, beyond thevariations provided for in the approved application.

2. A change in the labeling to provide for a new indication foruse of the drug product, if clinical studies are required tosupport the new indication for use.

3. A change in the labeling to provide for a new dosage regimenor for an additional dosage regimen for a special patientpopulation, e.g., infants, if clinical studies are required tosupport the new or additional dosage regimen.

320.22 Criteria for waiver of evidence of in vivo bioavailabilityor bioequivalence. 320.23 Basis for demonstrating in vivo bioavailability or

bioequivalence. 320.24 Types of evidence to establish bioavailability or

bioequivalence.

This section covers the different types of in vivo and in vitromethods that can be used to determine bioavailability and

bioequivalence. They are ranked in descending order ofaccuracy, sensitivity and reproducibility as stated or summarizedas follows:

1. i. An in vivo test in humans in which the concentration ofthe active ingredient or active moiety, and, whenappropriate, its active metabolite(s), in whole blood,



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plasma, serum, or other appropriate biological fluid ismeasured as a function of time,

ii. An in vitro test that has been correlated with and ispredictive of human bioavailability data; or

iii. An in vivo test in animals that has been correlated withand is predictive of human bioavailability data.

2. An in vivo test in humans in which the urinary excretion of theactive moiety, and, when appropriate, its active metabolite(s),are measured as a function of time.

3. An in vivo test in humans in which an appropriate acutepharmacological effect of the active moiety, and, when

appropriate, its active metabolite(s), are measured as afunction of time if such effect can be measured with sufficientaccuracy, sensitivity, and reproducibility.

4. Well-controlled clinical trials in humans that establish thesafety and effectiveness of the drug product, for purposes ofestablishing bioavailability, or appropriately designedcomparative clinical trials, for purposes of establishingbioequivalence.

5. A currently available in vitro test acceptable to FDA (usually adissolution rate test) that ensures human in vivo bioavailability.

6. Any other approach deemed adequate by FDA to establishbioavailability and bioequi valence.

320.25 Guidelines for the conduct of an in vivo bioavailabilitystudy.

Subheadings for the subsections under this section include:

a. Guiding principles.b. Basic design.c. Comparison to a reference material.d. Previously unmarketed active drug ingredients or therapeutic

moieties.e. New formulations of active drug ingredients or therapeutic

moieties approved for marketing.

f. Controlled release formulations.g. Combination drug products.h. Use of a placebo as the reference material.i. Standards for test drug product and reference material.

Related to subsection (d) that addresses previously unmarketedactive drug ingredients or therapeutic moieties, it states that the



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purpose of an in vivo bioavailability study is to determine thebioavailability of the formulation proposed for marketing aswell as to determine essential pharmacokinetic characteristics ofthe active drug ingredient or therapeutic moiety such as rate ofabsorption, extent of absorption, half-life, excretion,metabolism, and dose proportionality. It further indicates thatsuch characterization is a necessary part of the investigation ofthe drug to support drug labeling.

Under the umbrella to support drug labeling as outlined in thissubsection, and with the experience that has been obtained overtime since implementation of the BA and BE Requirements,

along with advances in technology, updated and addedinformation needs, in the realm of clinical pharmacology andbiopharmaceutics (as defined above and under the purview of 21CFR 320), are being asked to be addressed by sponsors in theirdrug development programs for new products. As will becovered in the section that discusses FDA guidances, FDAprovides more current thinking on such information needs asrelated to the different aspects of clinical pharmacology and

biopharmaceutics. (Note: Likewise in ICH guidelines, they toopresent and expand upon information needs in the areas ofclinical pharmacology and biopharmaceutics for drug productregistration, most of which is consistent with FDA guidances.)

320.26 Guidelines on the design of a single-dose in vivobioavailability study.

320.27 Guidelines on the design of a multiple-dose in vivobioavailability study.

21 CFR 300.50Combination Drugs

Under this CFR part it addresses fixed-combination prescription drugs forhumans. It states that Two or more drugs may be combined in a singledosage form when each component makes a contribution to the claimedeffects and the dosage of each component (amount, frequency, duration) issuch that the combination is safe and effective for a significant patient

population requiring such concurrent therapy as defined in the labeling forthe drug. It further explains that special cases of this general rule are wherea component is added (i) to enhance the safety or effectiveness of theprincipal active component and (ii) to minimize the potential for abuse ofthe principal active ingredient.



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Related to 21 CFR 300.50 from a clinical pharmacology andbiopharmaceutics perspective, specifically for the scenario where the newcombination product is to be administered as an alternative to giving two ormore currently marketed, single ingredient products, one is referred to 21CFR 320.25 (g) as identified above. Here it indicates that an in vivobioavailability study is needed to determine if the rate and extent ofabsorption of each active drug ingredient or therapeutic moiety of thecombination product is equivalent to the rate and extent of absorption ofeach active drug ingredient or therapeutic moiety administered concurrentlyin separate single-ingredient preparations. Information to address drug-drug interaction implications for the two or more drugs in a combinationproduct is also usually needed.

21 CFR 312Investigational New Drug Application

Within 21 CFR 312, some of what is presented is addressed in Section 505(i)

expanded and more detailed information related to INDs is given (e.g.,information related to IND content and format, type of IND amendments

and reports, administrative related actions, responsibilities of sponsors andinvestigators, etc.).

Of note, under Section 312.21, it indicates that the clinical investigationof a previously untested drug is generally divided into three phases (Phases1, 2, and 3). In general the phases are carried out sequentially but they mayoverlap.

Phase 1 is where the initial introduction of an investigational new druginto humans occurs. The studies in Phase 1 are designed to determine the

metabolism and pharmacologic actions of the drug, side effects associatedwith increasing doses and, if possible, obtain early evidence of effectiveness.Ideally, sufficient information about the drugs pharmacokinetics andsystemic exposure plus pharmacological effects or pharmacodynamicsshould be obtained to permit the design of well-controlled, scientificallysound Phase 2 studies. The number of subjects or patients used in Phase 1studies can vary with the drug but is usually in the range of 2080.

Phase 2 is where well-controlled clinical studies are conducted to evaluate

the effectiveness of the drug for a particular indication or indications inpatients with the disease or condition under study. Also determined are theshort-term side effects or risks associated with the drug or product. Thenumber of patients used in Phase 2 studies is usually no more than severalhundred.

Phase 3 studies include controlled and uncontrolled trials that areintended to gather additional information about effectiveness and safety for


ofChapter V of the FDCA as covered above. However, within 21 CFR 312


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evaluating the drugs overall benefit-risk relationship and to provideadequate information for labeling. Phase 3 studies can include from severalhundred to thousands of patients.

Ultimately when an NDA is submitted to FDA, it includes all of thestudies that have been carried out in Phases 1, 2, and 3. Human clinicalpharmacology and biopharmaceutics information is most often obtainedfrom studies that are conducted as Phase 1 type studies, but with theadvent of important and useful ways to analyze and model PK and PDdata, including population PK and PD statistical approaches,information can and is being obtained in Phase 2 and 3 studies. There areFDA and ICH guidances and guidelines summarized below, which giveinsight into this.

Lastly, in Section 312.85 there is discussion on Phase 4 studies. At the timeFDA is considering giving an NDA approval it may, with concurrence fromthe NDA sponsor, request that an additional postmarketing study or studiesbe conducted to delineate additional information about the drugs risks,benefits, and optimal use. Phase 4 type studies can be and are requested toobtain additional clinical pharmacology- or biopharmaceuticsrelatedinformation if warranted.

21 CFR 314Applications for FDA Approval to Market a New

Drug or an Antibiotic Drug

Like for 21 CFR 312, some of what is covered in 21 CFR 314 as related toapplications for market approval for a new drug is also covered in Sections

more expansive and specific in addressing NDAs (and AND As) as to theprocedures and requirements for the submission to, and for the review by

FDA of such applications for approval. Also addressed are amendments,supplements, and postmarketing reports to applications.

Under 314.2 it states that the purpose of 21 CFR 314 is to establish anefficient and thorough drug review process in order to (i) facilitate theapproval of drugs shown to be safe and effective and (ii) ensure thedisapproval of drugs not shown to be safe and effective. Additionally, itaddresses the establishment of a system for FDAs surveillance of marketeddrugs. Via Section 314.50 it covers the content and format of an NDA

application that is to include summary sections and technical sections forthe areas of (i) chemistry, manufacturing, and controls, (ii) nonclinicalpharmacology and toxicology, (iii) human pharmacokinetics andbioavailability, (iv) microbiology, and (v) clinical data along with statisticalanalyses.

For clinical pharmacology and biopharmaceutics related information,314.50(d)(3) indicates that a technical section should include human


505(b) and (j) ofChapter V of the FDCA. However, 21 CFR 314 is much


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pharmacokinetic data and human bioavailability data, or informationsupporting a waiver of the submission of in vivo bioavailability data ascovered under 21 CFR 320. Further it indicates that a description of eachof the human pharmacokinetic and bioavailability studies performed byor on behalf of the applicant should be provided along with a descriptionof the analytical and statistical methods used plus a statement related toinformed consent procedures used per study. Additionally, if theapplication describesin the chemistry, manufacturing, and controlssectionsspecifications or analytical methods needed to assure thebioavailability of the drug product or drug substance, or both, astatement of the rationale for establishing the specifications or analyticalmethods, including data and information supporting the rationaleshould be provided. Lastly, it is indicated that there should besummarizing discussion and analysis of the pharmacokinetics andmetabolism of the active ingredients and the bioavailability orbioequivalence, or both, of the drug product. In addition to what iscovered in 21 CFR 314, 21 CFR 320 plus FDA guidances and ICHguidelines should additionally be consulted to get further insight as towhat specific clinical pharmacology and biopharmaceutics informationand data should be provided in an NDA.

FDA GUIDANCES

Like the FR and CFR that are often used to better clarify or define the intent,expectations, or what is needed or required to comply with or enforce theFDCA, FDA, as already noted, prepares and publishes guidances thatprovide further insight, direction, and the Agencys current thinking on how

to best satisfy the FDCA and FR/CFR rules or regulations, albeit that FDAguidances are not legally binding. FDA guidances also attempt to establishuniformity and consistency as to what is needed in NDAs for submission.5

Key FDA guidances [http://www.fda.gov/cder/guidance ] that addressdifferent aspects of clinical pharmacology and biopharmaceutics, aspreviously defined, are covered.

Please note that only the guidances that are posted as final on theCDER web page are summarized below and the reader is encouraged to

look up guidances that are posted but are at the draft stage. Additionally,several of these final guidances deal with either a particular drug productor a specific therapeutic area and therefore are not considered in thischapter; only the final guidances that cover the general, broad-basedprinciples which apply to majority of the drug products and therapeuticareas are summarized below.

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Clinical Pharmacology

Format and Content of the Human Pharmacokinetics and

Bioavailability Section of an Application Guidance (1997)

This guidance is actually a reissuance of the guideline with the same titlethat was issued in 1987 and is intended to assist applicants to prepare theHuman Pharmacokinetics and Bioavailability section of an NDA. Afterproviding a brief overview of what types of studies are generally expectedfor NDAs, the guidance provides the outline of format for this section. Thesection should contain, in a tabular presentation, a summary of thestudies, data, and overall conclusions, drug formulation, analytical

methods, and a product in vitro release method (e.g., dissolution) ifappropriate. The tabular format, with columns identifying specificvariables for each of these components, is provided in the appendix.Finally, individual study report format and other considerations arecovered. It should be noted that even though the guideline was createdalmost 15 years ago, this is an excellent document and the formattingrecommendations conveyed here are followed, as a minimum, to date bymost applicants.

For last several years, there has been a lot of activity and extremelythoughtful efforts at the ICH level and a recently issued ICH guideline calledthe common technical document (CTD) provides an expanded and updatedversion of this guideline. This and other relevant ICH documents arecovered later in the chapter.

Guideline for the Study of Drugs Likely to be used in theElderly (1989)

Even though written 12 years ago with the primary intent to advice sponsorson how to undertake clinical investigation of drugs likely to be used in theelderly, this guideline is a milestone in terms of identifying, explaining, andrecommending clinical pharmacology studies in terms of drug-druginteractions, drug-disease interactions, special populations (elderly, renallyimpaired and hepatically impaired), and pharmacodynamic studies (in theelderly). Further, this guideline also established the concept of

Pharmacokinetic Screen which has subsequently matured into the scienceof Population Pharmacokinetics. In view of the authors, this is a must-read classical document. Not surprisingly, this is also one of the first topicsthat were finalized at the ICH and in view of the authors, the E7 document,namely Clinical Trials in Special PopulationsGeriatrics is an excellentupdate of this 89 document. The E7 document is covered in detail later onin the chapter.



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Drug Metabolism/Drug Interaction Studies in the DrugDevelopment Process: Studies In Vitro Guidance (1998)

This guidance is directed towards a broad class of drugs, namely molecules

with a molecular weight below 10 kilo Daltons, and it provides suggestionson current approaches to in vitro studies of metabolism and interactions ofsuch molecules. The guidance is intended to encourage routine, thoroughevaluation of metabolism and interactions in vitro whenever feasible andappropriate. This guidance recognizes that the importance of such anapproach will vary depending on the drug in development and its intendedclinical use. It also recognizes that clinical observations can address some ofthe same issues identified in this document as being susceptible to in vitro

study.The guidance covers the following topics: observations and

conclusions; techniques and approaches for in vitro studies for drugmetabolism and drug-drug interactions (DDI); correlations betweenstudies in vitro and in vivo; timing of metabolism studies; labeling; andrelated applications and considerations. This subject is discussed in detailin Chapter 6 of this book.

In Vivo Drug Metabolism/Drug Interaction StudiesStudyDesign, Data Analysis, and Recommendations for Dosingand Labeling Guidance (1999)

This guidance provides recommendations to sponsors of NDAs andbiologies license applications (BLAs) for therapeutic biologies (hereafterdrugs) who intend to perform in vivo drug metabolism and metabolicdrug-drug interaction studies. The guidance reflects the Agencys current

view that the metabolism of an investigational new drug should be definedduring drug development and that its interactions with other drugs shouldbe explored as part of an adequate assessment of its safety andeffectiveness. For metabolic drug-drug interactions, the approachesconsidered in the guidance are offered with the understanding thatwhether a particular study should be performed will vary, depending onthe drug in development and its intended clinical use. Furthermore, notevery drug-drug interaction is metabolism-based, but may arise from

changes in PK caused by absorption, tissue, and/or plasma binding,distribution and excretion interactions. Drug interactions related totransporters or pharmacodynamic-based drug interactions are notcovered in this guidance.

After a brief discussion on metabolism and metabolic DDIs, the guidancecovers the following topics: general strategies; design of in vivo metabolicdrug-drug interaction studies; and labeling.

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Pharmacokinetics in Patients with Impaired RenalFunctionStudy Design, Data Analysis, and Impacton Dosing and Labeling Guidance (1998)

This guidance is intended for sponsors who, during the investigational phaseof drug development, plan to conduct studies to assess the influence of renalimpairment on the PK of an investigational drug. Topics covered in thisguidance are: deciding whether to conduct a study in patients with impairedrenal function (when studies may be important, when studies may not beimportant); study design (basic full study design, reduced/staged studydesign, population PK studies, effect of dialysis on PK, PD assessments);data analysis (parameter estimation, modeling the relationship between renal

function and PK, development of dosing recommendations); and labeling(clinical pharmacology, precautions/warnings, dosage and administration,overdosage).

Population Pharmacokinetics Guidance (1999)

This guidance makes recommendations on the use of population PK in the

drug development process to help identify differences in drug safety andefficacy among population subgroups. It summarizes scientific andregulatory issues that should be addressed using population PK. Theguidance discusses when to perform a population PK study and/or analysis;how to design and execute a population PK study; how to handle andanalyze population PK data; what model validation methods are available;and how to provide appropriate documentation for population PK reportsintended for submission to the FDA.

Pharmacokinetics in Patients with Impaired HepaticFunction: Study Design, Data Analysis, and Impact onDosing and Labeling Guidance (2002)

This guidance provides recommendations to sponsors planning to conductstudies to assess the influence of hepatic impairment on the PK and, where

appropriate, PD of drugs or therapeutic biologies. This guidance addresses:when studies are and may not be recommended; the design and conduct ofstudies to characterize the effects of impaired hepatic function on the PK ofa drug; characteristics of patient populations to be studied; and analysis,interpretation, and reporting of the results of the studies and description ofthe results in labeling.



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Biopharmaceutics

Bioanalytical Method Validation Guidance (2001)

This guidance provides assistance to sponsors of INDs, NDAs, AND As,and supplements in developing bioanalytical method validation informationused in human clinical pharmacology, BA, and BE studies requiring PKevaluation. This guidance also applies to bioanalytical methods used fornonhuman pharmacology/toxicology studies and preclinical studies. Forstudies related to the veterinary drug approval process, this guidance appliesonly to blood and urine BA, BE, and PK studies. The information in thisguidance generally applies to bioanalytical procedures such as gaschromatography (GC), high-pressure liquid chromatography (LC),combined GC and LC mass spectrometric (MS) procedures such as LC-MS,LC-MS-MS, GC-MS, and GC-MS-MS performed for the quantitativedetermination of drugs and/or metabolites in biological matrices such asblood, serum, plasma, or urine. This guidance also applies to otherbioanalytical methods, such as immunological and microbiologicalprocedures, and to other biological matrices, such as tissue and skinsamples. The guidance touches upon the full, partial, and cross validationand then covers the following topics in detail: reference standard; method

development (chemical as well as microbiological and ligand-bindingassays); application of validated method to routine drug analysis; anddocumentation.

Dissolution Testing of Immediate Release Solid Oral Dosage

Forms Guidance (1997)

This guidance is intended to provide (i) general recommendations for

dissolution testing; (ii) approaches for setting dissolution specificationsrelated to the biopharmaceutic characteristics of the drug substance; (iii)statistical methods for comparing dissolution profiles; and (iv) a process tohelp determine when dissolution testing is sufficient to grant a waiver for anin vivo bioequivalence study. This document also provides recommendationsfor dissolution tests to help ensure continuous drug product quality andperformance after certain postapproval manufacturing changes.Information on dissolution methodology, apparatus, and operating

conditions for dissolution testing of IR products is provided in summaryform in Appendix A. This guidance is intended to complement the SUPACIR guidance for industry (Immediate Release Solid Oral Dosage Forms:Scaleup and Post-Approval Changes: Chemistry, manufacturing andControls, In Vitro Dissolution Testing, and In Vivo BioequivalenceDocumentation) with specific reference to the generation of dissolutionprofiles for comparative purposes.



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The topics covered in this guidance are: biopharmaceutics classificationsystem; setting dissolution specifications; dissolution profile comparisons;dissolution and SUPAC-IR; and biowaivers.

Extended Release Oral Dosage Forms: Development,

Evaluation, and Application of in vitro/in vivo CorrelationsGuidance (1997)

This guidance provides recommendations to pharmaceutical sponsors whointend to develop documentation in support of an in vitro/in vivocorrelation (IVIVC) for an oral extended release (ER) drug product forsubmission in an NDA or ANDA. The guidance presents a comprehensiveperspective on (i) methods of developing an IVIVC and evaluating itspredictability; (ii) using an IVIVC to set dissolution specifications; and (iii)applying an IVIVC as a surrogate for in vivo bioequivalence when it isnecessary to document bioequivalence during the initial approval process orbecause of certain pre or postapproval changes (e.g., formulation,equipment, process, and manufacturing site changes).

The topics covered in this guidance are: categories of in vitro/in vivocorrelations; general considerations; development and evaluation of a level

A in vitro/in vivo correlation; development and evaluation of a level Ccorrelation; and applications of an IVIVC.

Waiver of In Vivo Bioavailability and Bioequivalence Studies forImmediate-Release Solid Oral Dosage Forms Based on a

Biopharmaceutics Classification System Guidance (2000)

This guidance provides recommendations for sponsors of INDs, NDAs,

ANDAs, and supplements to these applications who wish to request awaiver of in vivo BA and/or BE studies for IR solid oral dosage forms. Thesewaivers are intended to apply to (i) subsequent in vivo BA or BE studies ofimmediate-release (IR) formulations after the initial establishment of in vivoBA during the IND phase and (ii) in vivo BE studies of IR oral dosage formsin ANDAs. In addition to the regulations at 21 CFR 320 that addressbiowaivers, this guidance explains when biowaivers can be requested for IRsolid oral dosage forms based on an approach termed the Biopharmaceutics

Classification System (BCS).The topics covered in this guidance are: the biopharmaceutics classification

system; methodology for classifying a drug substance and for determiningthe dissolution characteristics of a drug product; additional considerationsfor requesting a biowaiver; regulatory applications of the BCS; and data tosupport a request for biowaivers.



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Statistical Approaches to Establishing BioequivalenceGuidance (2001)

This guidance provides recommendations to sponsors and applicants who

intend, either before or after approval, to use equivalence criteria inanalyzing in vivo or in vitro BE studies for INDs, NDAs, ANDAs, andsupplements to these applications. This guidance discusses three approachesfor BE comparisons: average, population, and individual. The guidancefocuses on how to use each approach once a specific approach has beenchosen. This guidance replaces a prior FDA guidance entitled StatisticalProcedures for Bioequivalence Studies Using a Standard Two-TreatmentCrossover Design, which was issued in July 1992.

The topics covered in this guidance are: statistical model; statisticalapproaches for bioequivalence; study design; statistical analysis; andmiscellaneous issues.

Bioavailability and Bioequivalence Studies for Orally AdministeredDrug ProductsGeneral Considerations Guidance (2000)

This guidance is intended to provide recommendations to sponsors or

applicants planning to include BA and BE information for orallyadministered drug products in the INDs, NDAs, ANDAs, and theirsupplements. This guidance addresses how to meet the BA and BErequirements set forth in 21 CFR 320 as they apply to dosage formsintended for oral administration. These include tablets, capsules, solutions,suspensions, conventional/immediate release, and modified (extended/delayed) release drug products. The guidance is also generally applicable tononorally administered drug products where reliance on systemic exposure

measures is suitable to document BA and BE (e.g., transdermal deliverysystems and certain rectal and nasal drug products).This guidance starts with the definitions and a detailed discussion of the

terms BA and BE which is then followed by a discussion on the followingtopics: methods to document BA and BE; comparison of BA measures in BEstudies; documentation of BA and BE; and special topics namely food-effectstudies, moieties to be measured, long half-life drugs, first point Cmax,orally administered drugs intended for local action and narrow therapeutic

range drugs.This guidance is designed to reduce the need for FDA drug-specific BA/BEguidances. As a result, this guidance replaces a number of previously issuedFDA drug-specific guidances which are listed in the Appendix 1 of thisguidance.

A concluding remark on the U.S. regulations and guidances is that thereare a few pertinent guidances which are at the draft stage that are not



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covered in this chapter and the reader is strongly encouraged to get familiarwith them and follow their progress till issuance of the final version.Probably the most critical ones are the Exposure-Response and theFood-Effect guidances.

ICH GUIDELINES

With the globalization of the pharmaceutical industry, efforts have beenunderway since 1990 to standardize drug applications in terms of contentand format such that an application can be registered in different countrieswithout being subjected to different registration requirements amongcountries. Via efforts that include the participation of the European Union,Japan, and the United States, ICH guidelines have been prepared or are inthe process of being finalized on the topics of Quality (the Q series ofguidelines), Safety (the S series of guidelines), Efficacy (the E series ofguidelines), and Multidisciplinary (the M series of guidelines). Care has beentaken while reaching consensus with the other world bodies that theinformation that is needed is based on U.S. laws and CFR regulations plussimilar considerations for the other world regulatory agencies. Relevant

ICH guidelines [http://www.ifpma.org/ichl] as related to this chapter whichare either completed or at advanced stages of completion (step 4) arecovered.6

The order of presentation of these guidelines is based on their completiondates (earliest to latest) and not the sequence number given by the ICH (e.g.,E3 followed by E4, etc.). The reason is that it appears that clinicalpharmacology and biopharmaceutic concepts, and related recommendations,got introduced in the earliest guidelines in a broad and diffused sense and

they subsequently got elaborated upon and covered in more detail in laterguidelines.

E7: Studies in Support of Special Populations: Geriatrics

Guideline (1993)

As stated earlier, it appears that this guideline is modeled after an updatedversion of, the U.S. elderly guidance of 1989. It covers PK studies (formal

or a PK screen) in the elderly as well as renally or hepatically impairedpatients, PD/Dose-response studies and drug-drug interaction studies asfollows.

Pharmacokinetic Studies

The guideline states that most of the recognized important differencesbetween younger and older patients have been pharmacokinetic differences,

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often related to impairment of excretory (renal or hepatic) function or todrug-drug interactions. It is important to determine whether or not thepharmacokinetic behavior of the drug in elderly subjects or patients isdifferent from that in younger adults and to characterize the effects ofinfluences, such as abnormal renal or hepatic function, that are morecommon in the elderly even though they can occur in any age group.Information regarding age-related differences in the pharmacokinetics ofthe drug can come, at the sponsors option, either from a PharmacokineticScreen or from formal pharmacokinetic studies, in the elderly and inpatients with excretory functional impairment.

The guideline recognizes that for certain drugs and applications (e.g.,some topically applied agents, some proteins) technical limitations such aslow systemic drug levels may preclude or limit exploration of age-relatedpharmacokinetic differences.

Pharmacokinetics in Renally or Hepatically Impaired Patients

As stated in the guideline, renal impairment is an aging-associated findingthat can also occur in younger patients. Therefore, it is a general principlethat drugs excreted (parent drug or active metabolites) significantly through

renal mechanisms should be studied to define the effects of altered renalfunction on their pharmacokinetics. Such information is needed for drugsthat are the subject of this guideline but it can be obtained in youngersubjects with renal impairment.

Similarly, drugs subject to significant hepatic metabolism and/orexcretion, or that have active metabolites, may pose special problems in theelderly. Pharmacokinetic studies should be carried out in hepaticallyimpaired young or elderly patient volunteers.

If a Pharmacokinetic Screen approach is chosen by the sponsor, and ifpatients with documented renal impairment or hepatic impairment(depending on the drugs elimination pattern) are included and the resultsindicate no medically important pharmacokinetic difference, thatinformation may be sufficient to meet this geriatric guidelines purpose.

Pharmacodynamic/Dose Response Studies

The guideline states that the number of age-related pharmacodynamicdifferences (i.e., increased or decreased therapeutic response, or side effects,at a given plasma concentration of drug) discovered to date is too small tonecessitate dose response or other pharmacodynamic studies in geriatricpatients as a routine requirement. Separate studies are, however, recommendedin the following situations:



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Sedative/hypnotic agents and other psychoactive drugs or drugswith important CNS effects, such as sedating antihistamines.

Where subgroup comparisons (geriatric versus younger) in thePhase 2/3 clinical trials database indicate potentially medicallysignificant age-associated differences in the drugs effectivenessor adverse reaction profile, not explainable by PK differences.

Drug-Drug Interaction Studies

As per the guideline, such interactions are of particular importance togeriatric patients, who are more likely to be using concomitant medicationsthan younger patients, but of course are not limited to this age group.Therefore it is a general principle, not specific to these guidelines, that incases where the therapeutic range (i.e., a range of toxic to therapeutic doses)of the drug or likely concomitant drugs is narrow, and the likelihood of theconcomitant therapy is great, that specific drug-drug interaction studies beconsidered. The studies needed must be determined case-by-case, but thefollowing are ordinarily recommended:

Digoxin and oral anticoagulant interaction studies, because somany drugs alter serum concentrations of these drugs, they are

widely prescribed in the elderly, and they have narrowtherapeutic ranges.

For drugs that undergo extens ive hepat ic metabol ism,determination of the effects of hepatic-enzyme inducers (e.g.,phenobarbital) and inhibitors (e.g., cimetidine).

For drugs metabolized by cytochrome P-450 enzymes, it iscritical to examine the effects of known inhibitors, such asquinidine (for cytochrome P-450 2D6) or ketoconazole and

macrolide antibiotics (for drugs metabolized by cytochrome P-450 3A4). There is a rapidly growing list of drugs that caninterfere with other drugs via metabolism, and sponsors shouldremain aware of it.

Interaction studies with other drugs that are likely to be usedwith the test drug (unless important interactions have been ruledout by a Pharmacokinetic Screen).

E4: Dose-Response Information to Support Drug

Registration Guideline (Step 4; 1994)

This guideline covers the following topics: (i) introduction (purpose ofdoseresponse information, use of dose-response information in choosingdoses, use of concentration-response data, problems with titration designs,interaction between dose-response and time), (ii) obtaining dose-response



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information (dose-response assessment should be an integral part of drugdevelopment, studies in life-threatening diseases, regulatory considerationswhen dose-response data are imperfect, examining the entire database fordose-response information), (iii) study designs for assessing dose-response(general, specific trial designs), and (iv) guidance and advice.

The reader is strongly encouraged to read this guideline since it lays outthe fundamental value and benefit of the exposure (i.e., dose and/orconcentration)response information in drug development and evaluation,and recognizes past inadequacies as well as practical limitations ingeneration of this information base. As per the guideline, where a drug canbe safely and effectively given only with blood concentration monitoring,the value of concentration-response information is obvious. In other cases,an established concentration-response relationship is often not needed, butmay be useful for ascertaining the magnitude of the clinical consequences of(i) pharmacokinetic differences, such as those due to drug-disease (e.g., renalfailure) or drug-drug interactions, or (ii) for assessing the effects of thealtered pharmacokinetics of new dosage forms (e.g., controlled releaseformulation) or new dosage regimens without need for additional clinicaldata, where such assessment is permitted by regional regulations.Prospective randomized concentration-response studies are critical to

defining concentration monitoring therapeutic windows but are alsouseful when pharmacokinetic variability among patients is great; in thiscase, a concentration-response relationship may in principle be discerned ina prospective study with a smaller number of subjects than could be the doseresponse relationship in a standard dose-response study. Note thatcollection of concentration-response information does not imply thattherapeutic blood level monitoring will be needed to administer the drugproperly. Concentration-response relationships can be translated into

doseresponse information. Alternatively, if the relationships betweenconcentration and observed effects (e.g., an undesirable or desirablepharmacologic effect) are defined, patient response can be titrated withoutthe need for further blood level monitoring. Concentration-responseinformation can also allow selection of doses (based on the range ofconcentrations they will achieve) most likely to lead to a satisfactoryresponse.

E3: Structure and Content of Clinical Study Reports

Guideline (Step 4; 1995)

The relevant portions of this guideline from a clinical pharmacologyperspective are the sections which cover the drug concentrationmeasurements, drug dose, drug concentration, and relationships toresponse, and drug-drug and drug-disease interactions topics.



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Further discussion of this guideline is not undertaken in this chapter sincethese topics are also covered in other guidelines, particularly the M4guideline discussed later in this chapter.

E8: General Considerations for Clinical Trials Guideline

(1997)

This guideline goes over general principles of clinical trials in terms ofprotection of subjects and scientific approach in design and analysis, as wellas development methodology in terms of considerations for thedevelopment plan and considerations for individual clinical trials.

A very informative section in this guideline is Table 1 that provides anapproach to classifying clinical studies according to objectives. The tablebreaks down the types of studies into four categories, namely HumanPharmacology, Therapeutic Exploratory, Therapeutic Confirmatory, andTherapeutic Use and lists the objectives of such studies along with examples.The first two categories of studies identify clinical pharmacology studies.The Human Pharmacology category comprises studies that assess tolerance,define/describe PK and PD, explore drug metabolism and drug interactions,and enzyme activity. Examples of such studies are dose-tolerance studies,

single and multiple dose PK and/or PD studies, and drug interaction studies.Similarly, the Therapeutic Exploratory category consists of studies thatexplore use for the targeted indication, estimate dosage for subsequentstudies, provide basis for confirmatory study design, endpoints, andmethodologies. Examples of such studies are the earliest trials of relativelyshort duration in well-defined narrow patient populations, using surrogateor pharmacological endpoints of clinical measures, and dose-responseexploration studies.

Additional sections outlining clinical pharmacology and biopharmaceuticconsiderations are:

Quality of investigational medicinal products Phase I (Most typical kind of study: human pharmacology)

Estimation of initial safety and tolerability Pharmacokinetics Assessment of pharmacodynamics

Early measurement of drug activity

Special considerations Studies of drug metabolites Drug-drug interactions Special populations Investigations in nursing women



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E5: Ethnic Factors in the Acceptability of Foreign Clinical

Data Guideline (Step 4; 1998)

This guideline is based on the premise that it is not necessary to repeat an

entire clinical drug development program in a new region, and it is intendedto recommend strategies for accepting foreign clinical data as full or partialsupport for approval of an application in a new region. It is a strongendorsement of the utility of clinical pharmacology information. A coupleof key conceptsbridging study and compounds sensitive to ethnicfactorsin this guideline are based on, or utilize, clinical pharmacologyinformation. Additionally, it also provides a definition of a PK study, a PDstudy, and Population PK Methods as well as providing a good discussion of

PK, PD, and dose-response considerations.

Bridging Study

A bridging study is defined as a supplemental study performed in the newregion to provide pharmacodynamic or clinical data on efficacy, safety,dosage, and dose regimen in the new region that will allow extrapolation ofthe foreign clinical data to the new region. Such studies could include

additional pharmacokinetic information.Compounds Sensitive to Ethnic Factors

A compound whos pharmacokinetic, pharmacodynamic, or othercharacteristics suggest the potential for clinically significant impact byintrinsic and/or extrinsic ethnic factors [covered further in the M4 guideline]on safety, efficacy, or dose response.

Pharmacokinetic Study

A study of how a medicine is handled by the body, usually involvingmeasurement of blood concentrations of drug and its metabolite(s)(sometimes concentrations in urine or tissues) as a function of time.Pharmacokinetic studies are used to characterize absorption, distribution,metabolism, and excretion of a drug, either in blood or in other pertinentlocations. When combined with pharmacodynamic measures (a PK/PDstudy) it can characterize the relation of blood concentrations to the extent

and timing of pharmacodynamic effects.Pharmacodynamic Study

A study of a pharmacological or clinical effect of the medicine in individualsto describe the relation of the effect to dose or drug concentration. Apharmacodynamic effect can be a potentially adverse effect (anticholinergiceffect with a tricyclic), a measure of activity thought related to clinical



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benefit (various measures of beta-blockade, effect on ECG intervals,inhibition of ACE or angiotensin I or II response), a short-term desiredeffect, often a surrogate endpoint (blood pressure, cholesterol), or theultimate intended clinical benefit (effects on pain, depression, suddendeath).

Population Pharmacokinetic Methods

Population pharmacokinetic methods are a population-based evaluation ofmeasurements of systemic drug concentrations, usually two or more perpatient under steady state conditions, from all, or a defined subset of,patients who participate in clinical trials.

Pharmacokinetic, Pharmacodynamic, and Dose Response

Considerations

Evaluation of the pharmacokinetics and pharmacodynamics, and theircomparability, in the three major racial groups most relevant to the ICHregions (Asian, Black, and Caucasian) is critical to the registration ofmedicines in the ICH regions. Basic pharmacokinetic evaluation shouldcharacterize absorption, distribution, metabolism, excretion (ADME), and

where appropriate, food-drug and drug-drug interactions. Adequatepharmacokinetic comparison between populations of different regionsallows rational consideration of what kinds of further pharmacodynamicand clinical studies (bridging studies) are needed for the new region. Incontrast to the pharmacokinetics of a medication, where differencesbetween populations may be attributed primarily to intrinsic ethnic factorsand are readily identified, the pharmacodynamic response (clinicaleffectiveness, safety, and dose-response) may be influenced by both intrinsic

and extrinsic ethnic factors and this may be difficult to identify except byconducting clinical studies in the new region.

In general, dose-response (or concentration-response) should beevaluated for both pharmacologic effect (where one is considered pertinent)and clinical endpoints in a new foreign region. The pharmacologic effect,including dose-response, may also be evaluated in the foreign region in apopulation representative of the new region.

Depending on the situation, data on clinical efficacy and doseresponse in

the new region may or may not be needed, e.g., if the drug class is familiarand the pharmacologic effect is closely linked to clinical effectiveness anddose-response, the foreign pharmacodynamic data may be a sufficient basisfor approval and clinical endpoint and dose-response data may not beneeded in the new region. The pharmacodynamic evaluation, and possibleclinical evaluation (including dose-response), is important because of thepossibility that the response curve may be shifted in a new population.



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Examples of this are well documented, e.g., the decreased response in bloodpressure of blacks to angiotensin-converting enzyme inhibitors.

E11: Clinical Investigations of Medicinal Products in thePediatric Population Guideline (2000)

The sections of this guideline that outline the clinical pharmacologyinformation are:

Types of Studies

When a medicinal product is to be used in the pediatric population for thesame indication(s) as those studied and approved in adults, the diseaseprocess is similar in adults and pediatric patients, and the outcome oftherapy is likely to be comparable, therefore extrapolation from adultefficacy data may be appropriate. In such cases, pharmacokinetic studies inall the age ranges of pediatric patients likely to receive the medicinalproduct, together with safety studies, may provide adequate information foruse by allowing selection of pediatric doses that will produce blood levelssimilar to those observed in adults. If this approach is taken, adultpharmacokinetic data should be available to plan the pediatric studies.

When a medicinal product is to be used in younger pediatric patients forthe same indication(s) as those studied in older pediatric patients, the diseaseprocess is similar, and the outcome of therapy is likely to be comparable,therefore extrapolation of efficacy from older to younger pediatric patientsmay be possible. In such cases, pharmacokinetic studies in the relevant agegroups of pediatric patients likely to receive the medicinal product, togetherwith safety studies, may be sufficient to provide adequate information forpediatric use.

An approach based on pharmacokinetics is likely to be insufficient formedicinal products where blood levels are known or expected not tocorrespond with efficacy, or where there is concern that theconcentrationresponse relationship may differ between the adult andpediatric populations. In such cases, studies of the clinical or thepharmacological effect of the medicinal product would usually beexpected.

Where the comparability of the disease course or outcome of therapy in

pediatric patients is expected to be similar to adults, but the appropriateblood levels are not clear, it may be possible to use measurements of apharmacodynamic effect related to clinical effectiveness to confirm theexpectations of effectiveness and to define the dose and concentrationneeded to attain that pharmacodynamic effect. Such studies could provideincreased confidence that achieving a given exposure to the medicinalproduct in pediatric patients would result in the desired therapeutic



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outcomes. Thus, a PK/PD approach combined with safety and otherrelevant studies could avoid the need for clinical efficacy studies.

In other situations where a pharmacokinetic approach is not applicable,such as for topically active products, extrapolation of efficacy from onepatient population to another may be based on studies that includepharmacodynamic endpoints and/or appropriate alternative assessments.Local tolerability studies may be needed. It may be important to determineblood levels and systemic effects to assess safety.

Pharmacokinetics

Pharmacokinetic studies generally should be performed to supportformulation development and determine pharmacokinetic parameters indifferent age groups to support dosing recommendations. Relativebioavailability comparisons of pediatric formulations with the adult oralformulation typically should be done in adults. Definitive pharmacokineticstudies for dose selection across the age ranges of pediatric patients in whomthe medicinal product is likely to be used should be conducted in thepediatric population.

For medicinal products that exhibit linear pharmacokinetics in adults,

single-dose pharmacokinetic studies in the pediatric population mayprovide sufficient information for dosage selection. This can becorroborated, if indicated, by sparse sampling in multidose clinical studies.Any nonlinearity in absorption, distribution, and elimination in adults andany difference in duration of effect between single and repeated dosing inadults would suggest the need for steady state studies in the pediatricpopulation. All these approaches are facilitated by knowledge of adultpharmacokinetic parameters. Knowing the pathways of clearance (renal

and metabolic) of the medicinal product and understanding the age-relatedchanges of those processes will often be helpful in planning pediatric studies.

M4: The Common Technical Document for the Registration

of Pharmaceuticals for Human Use. EFFICACY. Module 2:

Clinical Overview and Clinical Summary. Module 5: Clinical

Study Reports (Step 4; 2000)

This is a very comprehensive guideline that identifies all important aspectsof clinical pharmacology and biopharmaceutic considerations and providesdetails on format and content of related requirements. In view of theauthors, this is a comprehensive update of the United States guideline issuedin 1987 and is a must-read.

As stated in the title, module 2 in this guideline goes over the organizationand content of the clinical overview and the clinical summary sections.



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Following this, module 5 provides organization of clinical study reports andrelated information. These reports are broken down into seven differentcategories: Biopharmaceutics Studies; Studies Pertinent to PK Using HumanBiomaterials; Human PK Studies; Human PD Studies; Efficacy and SafetyStudies; Postmarketing Experience; Case Report Forms; and IndividualPatient Listings. The first four of these report types form the basis forclinical pharmacology and biopharmaceutics information required in anapplication and are covered in detail below:

Biopharmaceutic Studies

This guideline states that bioavailability studies evaluate the rate and extentof release of the active substance from the medicinal product. ComparativeBA or BE studies may use PK, PD, clinical, or in vitro dissolution endpoints,and may be either single dose or multiple dose. Types of BA studiesidentified are (i) studies comparing the release and systemic availability of adrug substance from a solid oral dosage form to the systemic availability ofthe drug substance given intravenously or as an oral liquid dosage form, (ii)dosage form proportionality studies, and (iii) food-effect studies. Next set ofstudies identified are comparative BA and BE studies, and these are studies

that compare the rate and extent of release of the drug substance fromsimilar drug products (e.g., tablet to tablet, tablet to capsule). ComparativeBA or BE studies may include comparisons between (i) the drug productused in clinical studies supporting effectiveness and the to-be-marketed drugproduct, (ii) the drug product used in clinical studies supportingeffectiveness and the drug product used in stability batches, and (iii) similardrug products from different manufacturers. The final type of studiesidentified are In VitroIn Vivo Correlation studies, i.e., in vitro dissolution

studies that provide BA information, including studies used in seeking tocorrelate in vitro data with in vivo performance.

Studies Pertinent to Pharmacokinetics Using Human Biomaterials

The guideline defines human biomaterials as proteins, cells, tissues, andrelated materials derived from human sources, which are used in vitro or exvivo to assess PK properties of drug substances. The types of studies

identified are plasma protein binding studies, and hepatic metabolism anddrug interaction studies. Examples include cultured human colonic cells thatare used to assess permeability through biological membranes and transportprocesses, and human albumin that is used to assess plasma protein binding.Of particular importance is the use of human biomaterials such ashepatocytes and/or hepatic microsomes to study metabolic pathways and toassess drug-drug interactions with these pathways.



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Human Pharmacokinetic Studies

According to the guideline, assessment of the PK of a drug in healthysubjects and/or patients is considered critical to designing dosing strategies

and titration steps, to anticipating the effects of concomitant drug use, andto interpreting observed pharmacodynamic differences. These assessmentsshould provide a description of the bodys handling of a drug over time,focusing on maximum plasma concentrations (peak exposure), area-undercurve (total exposure), clearance, and accumulation of the parent drugand its metabolite(s), in particular those that have pharmacological activity.The PK studies are generally designed to (i) measure plasma drug andmetabolite concentrations over time, (ii) measure drug and metabolite

concentrations in urine or feces when useful or necessary, and/or (iii)measure drug and metabolite binding to protein or red blood cells.

On occasion, PK studies may include measurement of drug distributioninto other body tissues, body organs, or fluids (e.g., synovial fluid orcerebrospinal fluid). These studies should characterize the drugs PK andprovide information about the absorption, distribution, metabolism, andexcretion of a drug and any active metabolites in healthy subjects and/orpatients. Studies of mass balance and changes in PK related to dose (e.g.,

determination of dose proportionality) or time (e.g., due to enzymeinduction or formation of antibodies) are of particular interest. Additionalstudies can also assess differences in systemic exposure as a result of changesin PK due to intrinsic (e.g., age, gender, racial, weight, height, disease,genetic polymorphism, and organ dysfunction) and extrinsic (e.g., drug-drug interactions, diet, smoking, and alcohol use) factors. In addition tostandard multiple-sample PK studies, population PK analyses based onsparse sampling during clinical studies can also address questions about the

contributions of intrinsic and extrinsic factors to the variability in thedosePK-response relationship. Thus, the guideline identifies the followingtypes of studies as Human PK studies: Healthy subject PK and initialtolerability; Patient PK and initial tolerability; Intrinsic factor PK; Extrinsicfactor PK; and Population PK.

Human Pharmacodynamic Studies

The guideline identifies these as (i) studies of pharmacologic propertiesknown or thought to be related to the desired clinical effects (biomarkers),(ii) short-term studies of the main clinical effect, and (iii) PD studies of otherproperties not related to the desired clinical effect. Because a quantitativerelationship of these pharmacological effects to dose and/or plasma drugand metabolite concentrations is usually of interest, PD information isfrequently collected in dose response studies or together with drug



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concentration information in PK studies (concentration-response or PK/PDstudies). The guideline states that dose-finding, PD and/or PK-PD studiescan be conducted in healthy subjects and/or patients, and can also beincorporated into the studies that evaluate safety and efficacy in a clinicalindication. In some cases, the short-term PD, dose-finding, and/or PK-PDinformation found in pharmacodynamic studies conducted in patients willprovide data that contribute to assessment of efficacy, either because theyshow an effect on an acceptable surrogate marker (e.g., blood pressure) oron a clinical benefit endpoint (e.g., pain relief). Thus the studies identifiedhere are healthy subject PD and PK/PD studies plus patient PD and PK/PDstudies.

The reader must note that the guideline clearly states that when these PDstudies are part of the efficacy or safety demonstration, they are consideredclinical efficacy and safety studies that should be included in Section 5.Similarly, studies whose primary objective is to establish efficacy or toaccumulate safety should be included in Section 5.

Section 5 is beyond the scope of this chapter.

GLOSSARY

Bioavailability. The rate and extent to which the active ingredient or activemoiety is absorbed from a drug product and becomes available at the site ofaction. For drug products that are not intended to be absorbed into thebloodstream, bioavailability may be assessed by measurements intended toreflect the rate and extent to which the active ingredient or active moietybecomes available to the site of action.

Bioeqivalence. The absence of a significant difference in the rate and extentto which the active ingredient or active moiety in pharmaceuticalequivalents or pharmaceutical alternatives becomes available at the site ofdrug action when administered at the same molar dose under similarconditions in an appropriately designed study. Where there is an intentionaldifference in rate (e.g., in certain controlled release dosage forms), certainpharmaceutical equivalents or alternatives may be considered bioequivalentif there is no significant difference in the extent to which the active

ingredient or moiety from each product becomes available at the site of drugaction. This applies only if the difference in the rate at which the activeingredient or moiety becomes available at the site of drug action isintentional, is reflected in the proposed labeling, is not essential to theattainment of effective body drug concentrations on chronic use, and isconsidered medically insignificant for the drug.



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Drug. Means (i) articles recognized in the official United States Pharmacopoeia,official Homoeopathic Pharmacopoeia of the United States, or officialNational Formulary, or any supplement to any of them; and (ii) articlesintended for use in the diagnosis, cure, mitigation, treatment, or preventionof disease in man or other animals; and (iii) articles (other than food)intended to affect the structure or any function of the body of man or otheranimals; and (iv) articles intended for use as a component of any articlespecified in clause (i), (ii), or (iii); but does not include devices or theircomponents, parts, or accessories.

Drug Product. A finished dosage form, e.g., tablet, capsule, or solution, thatcontains the active drug ingredient, generally, but not necessarily, in

association with the inactive ingredients.

Extended Release. Extended release products are formulated to make thedrug available over an extended period after ingestion. This allows areduction in dosing frequency compared to a drug presented as aconventional dosage form (e.g., as a solution or an immediate release dosageform).

Immediate Release. Allows the drug to dissolve in the gastrointestinal

contents, with no intention of delaying or prolonging the dissolution orabsorption of the drug.

Interstate Commerce. Means (i) commerce between any State or Territoryand any place outside thereof, and (ii) commerce within the District ofColumbia or within any other Territory not organized with a legislativebody.

Labeling. All labels and other written, printed, or graphic matter (i) uponany article or any of its containers or wrappers, or (ii) accompanying sucharticle.

Modified Release Dosage Forms. Dosage forms whose drug-releasecharacteristics of time course and/or location are chosen to accomplishtherapeutic or convenience objectives not offered by conventional dosageforms such as a solution or an immedi

Documents

Regulatory Bases for Clinical Pharmacology and Biopharmaceutics Information in a New Drug Application