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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH Working with FDA: Biological Products and Clinical Development RAID Investigator.

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Presentation on theme: "U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH Working with FDA: Biological Products and Clinical Development RAID Investigator."— Presentation transcript:

1 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH Working with FDA: Biological Products and Clinical Development RAID Investigator Training – Clinical Trial Section II May 2007 Hong Zhao, Ph.D. Office of Clinical Pharmacology Office of Translational Science Center for Drug Evaluation and Research FDA

2 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Topics  Exploratory IND (ExIND) Guidance  Clinical Pharmacology Considerations for Therapeutic Biologic Products (TBPs) Review

3 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Exploratory IND (ExIND) Guidance

4 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Exploratory IND Guidance  Overview  Ideas and Concepts  Basic Outline of the ExIND  Projects as Outlined in ExIND Guidance Clinical investigation of biodistribution (pharmacokinetics) characteristics or imaging Clinical investigation of mechanisms of action (MOAs) related to efficacy Clinical investigation of pharmacological effects  Summary

5 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Overview  Existing regulations (21 CFR 321) allow for a great deal of flexibility in the amount of data to be submitted with IND applications depending on the intended goals of clinical study and the expected risks.  Exploratory IND (ExIND) is intended to clarify what chemistry, manufacturing and control (CMC) standards, pre-clinical testing and clinical approaches are needed when planning limited, early studies in humans.  This presentation concerns pre-clinical testing and clinical studies.

6 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Ideas and Concepts (1)  Not follow the typical or conventional mode of drug development. Addressed need to: Characterize new therapeutic targets Identify lead candidates from a portfolio to interact with a specific therapeutic target Examine biodistribution using various imaging technologies Perform ‘scouting’ studies of pharmacokinetics and/or pharmacodynamics in humans  Not intended to provide means of selecting a therapeutic dose, e.g., not an MTD study

7 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Ideas and Concepts (2)  Not intended to supplant a conventional IND  Upon completion of an ExIND ExIND is withdrawn If appropriate, investigative studies may be continued under a traditional IND supported by a full appropriate preclinical studies. Results should be discussed with the review division after closing the ExIND and prior to submission of a conventional IND.

8 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Ideas and Concepts (3) Benefits to the public health  Increase understanding of MOA associated with candidate selection  Emphasize and increase the contribution of science to the selection of drug candidates  Promote efficient and effective use of resources  Increase the number and rate of NME developed for patient use  Protect human subjects

9 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Basic Outline of the ExIND (1) Clinical Studies in ExINDs  Limited human exposure with no therapeutic or diagnostic intent (e.g., screening studies, micro dose studies)  Administration of either sub-pharmacologic doses or doses expected to produce a pharmacologic, but not a toxic effect  Limited number of human subjects with a limited dose range for a limited period of time  Less risk to human subjects than traditional Phase 1 studies that look for dose-limiting toxicities

10 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Basic Outline of the ExIND (2) Preclinical studies supporting ExINDs  Preclinical safety data required for ExIND will need to meet the proposed clinical study.  Reduction in safety data requirements will match the limited goals, duration and scope of the proposed clinical study.  Imaging studies can be initiated with much less preclinical support than is typically required for conventional IND studies.

11 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Basic Outline of the ExIND (3) Goals of preclinical studies  Qualitative (identification of target organs) and quantitative characterization of pharmacology and toxicology  Specific outcomes Initial starting dose High dose Tentative therapeutic index Dose escalation scheme Monitoring scheme

12 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao  Clinical investigation of biodistribution (pharmacokinetics) or imaging  Clinical investigation of mechanisms of action (MOAs) related to efficacy  Clinical investigation of pharmacological effects Projects as Outlined in the ExIND Guidance

13 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clinical Investigation of Biodistribution or Imaging (1) Clinical Studies  Use micro dosing concept for safety (at 1/100 th of pharmacological dose) Not designed to induce pharmacological effects Collect biodistribution (PK) information in human subjects Investigate specific targets of imaging agents Select compounds for further development  Involve single dose administration

14 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clinical Investigation of Biodistribution or Imaging (2) Supporting Preclinical Studies  Traditional IND Safety pharmacology studies Expanded acute toxicity studies in two mammalian species Standard battery of genotoxicity tests  ExIND Expanded acute toxicity studies in one mammalian species –Conducted using intended route of clinical administration –Single dose study in relevant species with a 14-day observation and interim sacrifice, full clinical and histopathology evaluation –No need to establish MTD

15 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clinical Investigation of MOAs Related to Efficacy Preclinical safety established by  Alternative or modified pharmacological and toxicological studies  Used to determine starting and ending clinical doses  Driven by MOA, e.g., degree of receptor saturation, but include endpoints used to assess toxicity  Incorporate documentation and procedures to allow an independent review of the data, e.g., protocol, SOPs and study report

16 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clinical Investigation of Pharmacological Effects (1)  Starting dose would be no greater than 1/50 the NOAEL from the 2-week toxicity study using the most sensitive species; extrapolated by body surface area conversion  Stopping dose would be whichever is lowest: Dose that induces pharmacological effect or target modulation ¼ of rat NOAEL as determined in the 2-week toxicity study ½ of AUC at the NOAEL for in rat 2-week study or ½ of dog AUC at the rat NOAEL (assume ‘real time’ measurement of plasma drug levels during clinical studies)

17 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clinical Investigation of Pharmacological Effects (2) Example (starting and stopping doses)  Drug tested in rats and dog 2-week p.o.  NOAEL Rat: 6 mg/kg, HED 1 mg/kg Dog: 20 mg/kg, HED 11 mg/kg  Actual clinical start dose: 0.02 mg/kg (1/50th rat NOAEL = 0.02 mg/kg)  Highest clinical dose tested: 1 mg/kg (1/4th rat NOAEL = 1.25 mg/kg)

18 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Summary (1)  CDER sees implementation of the ExIND guidance as vital part of FDA’s commitment to improving the “critical path” to new medical products.  Projects as outlined in the ExIND Guidance include clinical investigation of biodistribution (pharmacokinetics) or imaging, mechanisms of action (MOAs) related to efficacy, and pharmacological effects.

19 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Summary (2)  The preclinical safety data requirements for ExIND studies are less extensive than for conventional INDs.  Reduction in preclinical safety data requirements will be scaled to the goals, duration and scope of the proposed clinical studies.  Upon completion, ExIND is withdrawn.  If appropriate, studies may be continued under a conventional IND that is supported by a full appropriate battery of preclinical studies.

20 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clinical Pharmacology Considerations for Therapeutic Biologic Products (TBPs) Review

21 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clinical Pharmacology Considerations for Therapeutic Biologic Products (TBPs) Review  General Differences between Biologics and Small Molecule Drugs  Pharmacokinetic Characteristics of TBPs 1)Species specificity 2)Assay-dependent PK 3)Route, site and rate of administration 4)Volume of distribution and binding proteins 5)Receptor-mediated and/or immune-mediated clearance 6)Immunogenicity 7)Structure modifications (pegylation and glycosylation) 8)TBP-drug interactions  Summary

22 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao General Differences between Biologics and Small Molecules (1) Drug Substance (DS) and Drug Product (PD)

23 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao General Differences between Biologics and Small Molecules (2) Pharmacology*

24 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Well-known TBPs  Examples include but not limited to: Cytokines Plasminogen activators Recombinant plasma factors Growth factors Fusion proteins Enzymes Receptors Hormones Monoclonal antibodies

25 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Species Specificity and Receptor Related Disposition  Many TBPs are species specific and receptor(s) may be a factor in disposition. Antigen specificity limits ADME studies of humanized monoclonal antibodies in rodents. Animals may rapidly develop an immune response to recombinant human (rh)-proteins.

26 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Limitations of Assay Methodologies

27 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Route of Administration Oral:  Denaturation in acid pH of the stomach  Proteolytic degradation within GI  Minimal rates of diffusion through the GI epithelial due to large molecular size and high polarity IV:  Complete systemic availability  Rapid delivery to achieve high concentrations  Allowing administration of larger volumes  Less possibility of immunogenicity  Inconvenient, increasing cost, precipitating AEs with rapid infusion

28 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Route of Administration SC, IM:  Large doses may not be feasible due to the relatively limited solubility of IgG (  100 mg/mL), and pain associated with administration of volumes >2.5mL (SC) or 5mL (IM)  Large dose can be given by multiple injections  Viable for therapeutic antibodies that rapid absorption is not necessary and dose is not greater than 500 mg

29 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Route of Administration on PK Route of Administration (IV, IM, SC)  Molecular weight may play a role in absorption process.  Absolute bioavailability may be % depending on the extent of presystemic degradation by proteolytic enzymes.  Proteolytic degradation may be saturable leading to increases in bioavailability with increasing doses.  Absolute bioavailability may appear to be >100% (assay artifacts, formation of antibodies).  Different routes may produce different biological activity and adverse effects.

30 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Site and Rate of Administration on PK Site of Administration (arm, abdomen, thigh) rh-erythropoietin absorption: thigh > arm > abdomen GH Cmax: abdomen > thigh, similar AUC Rate of Administration (Intermittent, pulsed delivery, continuous infusion) Effectiveness of GH, parathyroid hormone, tPA: intermittent or pulsed delivery > continuous infusion Tumor inhibition of IL-2 in mice: 12 injections of 1,500 units > 2 doses of 9,000 units

31 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Volume of Distribution Distribution  After reaching the blood stream, a protein molecule is distributed intracellularly through the vascular space transporting across the microvascular wall through the interstitial space across cell membranes Volume of Distribution  For most TBP Vss is small and approximates the plasma volume (3-5% of TBW).  For TBP with higher affinity and higher capacity binding to cellular binding sites, Vd may be greater than plasma volume.  In case where binding capacity is limited, nonlinear distribution may be expected.

32 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Binding Proteins on PK Binding Proteins (Endothelial binding sites, free or shed receptors, macroglobulins, and other circulating molecules) may  have inhibitory or stimulatory effects  serve as transporters and activators  affect protein drug elimination

33 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clearance Clearance Pathways  Internalization  Formation of endosomes and lysosomes  Proteolytic degradation  Fc receptor (FcRn, Fcγ)-mediated  Cleavage to activate for blood coagulation cascade  No metabolites (amino acids recycled)  Non-cytochrome P450 substrates

34 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Elimination  Hepatocytes uptake (for large MW) Receptor-mediated endocytosis: specific and saturable Nonselective pinocytosis: nonsaturable, noncarrier- mediated  Biliary excretion, spleen, lymphatic  Renal excretion (for MW<69kDa) Filtered by the glomerulus and excreted (for MW<30kDa), reabsorbed back as intact or catabolic Peritubular extraction and hydrolysis Major form of elimination from circulation is binding to receptor/antigen and internalization

35 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Receptor-Mediated Clearance on PK  Receptor-mediated clearance may result in nonlinear PK due to receptor saturation.  Anti-TBP antibodies may alter PK of TBPs.

36 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Example: An MAb – Nonlinear PK with Dose

37 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Immunogenicity Anti-TBP antibody formation depends on  State of the host immune system (disease state)  Characteristics of the antigen (nonhuman sources, molecular size, structural complexity) Immunogenicity  with the extent of IgG humanization: “fully humanized” IgG < CDR-grafted IgG < chimeric IgG < rodent IgG  Dose, frequency and duration Immunogenicity  with  dose,  frequency,  duration  Route of administration SC > IM > IV, due to precipitation and aggregation  Complex and difficult to predict *Exceptions exist.

38 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Immunogenicity on PK, Efficacy and Safety  decrease pharmacological response through ‘neutralizing’ the TBP’s activity or increase its clearance (↑ CL)  sustain activity through decrease TBP’s clearance (↓CL)  cause adverse effects not directly related to the TBP (e.g., immune complex deposition)  cross-react with endogenous proteins  mask TBP’s detection Anti-TBP antibody formation may

39 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Anti-lenercept Antibodies on Lenercept PK

40 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Pegylation on PK, Efficacy and Safety (1) Pegylation may   t 1/2   CL   Toxicity   Immunogenicity   Drug stability and solubility   Biological activity *Exceptions exist: e.g., albumin’s t 1/2 is not changed by Pegylation Pegylation Polyethylene glycol (PEG): water soluble polymer, covalently linked to TBP, number of substitution may vary, over 40 known examples

41 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Pegylation on PK, Efficacy and Safety (2) Mechanisms of Pegylation Effects  Increased size above limit of glomerular filtration  Interference with interactions of carbohydrate chains with specific receptors (adds steric hindrance, reduce proteolysis)  Masking specific amino acids sequences which are cellular receptors (decrease biological activity)  Masking of antigenic sites (reduce immunogenicity and toxicity)

42 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Impact of Glycosylation on PK, Efficacy and Safety Glycosylation (Addition of certain sugar to a protein moiety) Glycosylation and biological function  Lymphocyte “homing”  Tumor invasiveness  Trophoblast implantation  Intracellular adhesion Post-translational modification  may be required for biological activity  regulates the ligand-receptor interaction and protein secretion  may alter PK  enhances protein stability

43 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao TBP-Drug Interactions (1) ICH Topic S6 (July 1997): The expected consequence of metabolism of biotechnology-derived pharmaceuticals is the degradation to small peptides and individual amino acids. Therefore, the metabolic pathways are generally understood. Classical biotransformation studies as performed for pharmaceuticals are not needed. (may need revisit)

44 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao TBP-Drug Interactions (2)  TBPs are non-P450 substrates  TBP-drug interaction studies are usually not required unless indicated  Some cytokines, including G-CSF may alter the PK and/or PD of other concomitant administered drugs  Possible inhibition or stimulation of P450 system through down-regulation of P450 gene transcription and RNA modulation  Magnitude of PK alteration relatively small and non- unidirectional  PD interaction more important TBP-drug interactions are rarely observed

45 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Summary 1)TBPs are species specific and receptors may affect their PK. 2)PK parameter estimates are largely assay- dependent. 3)Route, site and rate of administration may have an impact on PK of a TBP and may produce different biological activity and adverse effects. 4)Binding proteins may serve as transporters and activators, may have inhibitory or stimulatory effects, and may affect elimination of TBPs. 5)Receptor-mediated and/or immune-mediated clearance may result in non-constant clearance.

46 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Summary 6)Immunogenicity may have an impact on PK, efficacy and safety. 7)Pegylation may decrease clearance, reduce toxicity and immunogenicity, and increase stability and solubility. 8)Glycosylation may be required for biologic activity to regulate the ligand-receptor interaction and protein secretion, to enhance protein stability, and may alter PK profile. 9)Drug interactions are rarely observed, but some cytokines may inhibit or stimulate CYP450 system.

47 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Acknowledgments Dr. Dave Green Dr. Iftekhar Mahmood

48 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Quiz Questions

49 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Clinical Pharmacology Considerations for TBPs Review

50 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Question 1. (true or false) The expected consequence of metabolism of TBPs is the degradation to small peptides and individual amino acids; therefore, the metabolic pathways of TBPs are generally understood.

51 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Answer to Question 1: True (ICH S6)

52 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Question 2. (multiple choice) Which of the following characteristics does not belong to TBPs? (a) high molecular weight (b) highly targeted (c) species-specific (d) non-immunogenic

53 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Answer to Question 2: (d) TBPs are exogenous proteins and they are potentially immunogenic. Immunogenicity must be evaluated for each TBP.

54 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Question 3. (multiple choice) Which one of the following is the most appropriate statement? Anti-TBP antibodies may have the following effects on TBPs: (a) increase clearance (b) decrease clearance (c) decrease pharmacologic effect (d) increase infusion-associated reactions (e) all of above (f) none of above

55 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Answer to Question 3: (e)

56 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Exploratory IND Guidance

57 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Question 1. (true or false) Upon completion, the Exploratory IND is withdrawn. If appropriate, studies may be continued under a conventional IND that is supported by a full appropriate battery of preclinical studies.

58 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Answer to Question 1: (True)

59 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Question 2. (multiple choice) Which of the following statements describes basic outline of Exploratory INDs? (a)Limited human exposure with no therapeutic or diagnostic intent (e.g., screening studies, micro dose studies) (b) Administration of either sub-pharmacologic doses or doses expected to produce a pharmacologic, but not a toxic effect (c) Limited number of human subjects with a limited dose range for a limited period of time (d) Less risk to human subjects than traditional Phase 1 studies that look for dose-limiting toxicities (e) None of above (f) All of above

60 Working with FDA: Biological Products and Clinical DevelopmentHong Zhao Answer to Question 2: (f)


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