Phase 0 and Phase 1 clinical trial

Phase 0 and Phase 1 Clinical Trial

1. PHASE 0 AND PHASE 1 CLINICAL TRIAL Dr. Yash N. Panchal Junior Resident Department of Pharmacology AMC MET Medical college 02/09/2021

2. Presentation Layout History and introduction of clinical trial Pre-requisite to conduct clinical trial Phase 0 trial – Phase 1 trial - Purpose Purpose Features Objectives Objectives Study populations Procedures CPUs Analytical methods Formulations Advantages Parameters assessed Limitations 2

3. History of clinical trials 3

4. What is clinical trial ?? Any research study that prospectively assigns human participants or groups of human participants to one or more health related interventions to evaluate the effects on health outcomes (WHO) 4

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6. Objectives of clinical trial 6

7. Types of clinical trial 7

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9. Pre-requisites to conduct clinical trials A clinical trial can begin only when all preclinical studies shows satisfactory results , and approval has been received from DRA DRA - India ( DCGI ), USA( FDA ), UK( CSM ) Prior to conduct of a clinical trial, an IND must be filled with the DRA , to request permission to begin Human testing Filled by Sponsor /Manufacturer 9

10. INDA(Investigational new drug application ) 1. An introductory statement and general description of the plan for studying the drug or biologic 2. Source, chemical structure, manufacturing data and details on the purity of drug 3. Pre-clinical study details of the drug in terms of pharmacokinetics, pharmacodynamics, efficacy and toxicity 4. Specification on dosage forms in which it has to be administered to human volunteers 5. Description on dose and route of administration of the drug 10

11. INDA, Continued… 6. A certification that “ Informed consent ” will be obtained from each and every human volunteers and Ethics of research in human beings will be strictly followed 7. Names and qualifications of every investigators and facilities involved in clinical trial 8. An investigator’s brochure containing information pertaining to the investigational drug formulation, PK, PD, safety and toxicity from previous studies 9. Agreement from sponsor to submit annual progress report regularly 11

12. PHASE 0 OF CLINICAL TRIAL Why Phase 0 ?? Surveys had showed in R&D expenditure but numbers of INDA static/ Nearly one third of INDs failed in Phase 1 trial , mainly due to abnormal PK/PD and safety profiles If drug development, were to be terminated at Phase 1 stage , then human volunteers would have been unnecessarily exposed to failed drug and large number of animals would have been saved 12

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14. Continued… USFDA Birth of novel approach called Phase 0/ Micro-dosing studies The principle of human micro dosing is that safely administering micro-doses of INDs to human to get valuable information on human pharmacokinetics, pharmacodynamics at a much earlier stage Central to this approach is the concept that – “ the best model for man is man ” 14

15. How reliable are animal toxicity studies ?? 15

16. Micro-dose ?? Is dose of the drug that is 1% (1/100 th ) of the pharmacologically active dose determined from animal model and in vitro system, up to maximum of 100 mcg or 30 nanomole for protein products 16

17. PHASE 0/ MICRO-DOSING Because human micro dosing studies are performed prior to Phase 1 studies, hence are termed as Phase 0 study Are also termed as Exploratory IND studies Sub-pharmacologically active dose of drug is administered and samples (typically plasma) are collected and analyzed for parent drug or metabolites with no therapeutic or diagnostic intent 17

18. PURPOSE OF PHASE 0 TRIAL To assist the GO vs NO-GO decision making process of drug’s fate in the development process very earlier 18

19. Features of phase 0 trial First in human trial conducted prior to traditional Phase 1 study Conducted in limited number of Human participants (10-15) Have limited dosing duration (< 7 days ) Involves a very small dose ( 1/100 th of the dose required to yield a pharmacological effect of the test substance with a maximal dose of < 100 mcg Are designed to evaluate PK and/or PD properties of selected investigational agent before Phase 1 study Have no therapeutic or diagnostic intent Often take less than 6 months to complete 19

20. Objectives 1- To evaluate Pharmacokinetic and Pharmacodynamics of candidate drug 2- Evaluating human PK and/or PD of two or more analogs to select the most promising candidate for further clinical development 3- Eliminating bad agents early in clinical development because of poor PK or PD properties e.g- lack of target effect, poor bioavailability, rapid clearance of drug 4- Determining dose range, sequence of administration, and PK associated with target or biomarker (PK-PD correlation ) 20

21. Types of phase 0 studies 1- Pharmacokinetics or Imaging Evaluate human biodistribution and target-binding ( to molecular target and target tissues ) characteristics using sensitive imaging techniques Preclinical toxicology studies should demonstrate that a dose 100 times of the proposed dose does not induce adverse effects 2- Pharmacologically relevant dose Evaluate human PK of two or more analogues to select a lead agent 21

22. Continued.. 3- Pharmacodynamic end-point studies Evaluate whether the new molecular entity modulates its intended target 22

23. Procedure After the drug candidate has been selected and animal PK data is achieved, possible human therapeutic dose is determined A micro dosing clinical trial application ( Exploratory IND) should be submitted Micro dose is calculated from human therapeutic dose Bio markers and Bio-analytical methods should be determined, standardized and validated 23

24. Continued.. Phase 0 study involves 10-15 healthy volunteers, consent of them is taken Limited duration of dosing (e.g- 1-7 days ); in cancer chemotherapy usually one cycle only Bioanalytical samples are obtained pre- and post- dosing Samples are analyzed by bio-analytical methods for identification of the predetermined biomarkers 24

25. Analytical methods Low dose administered in Phase o study, will lead to low plasma-drug concentrations Therefore sensitive analytical methods are necessary in order to make the requisite measurements over an appropriate time Sensitive analytical technologies include AMS ( Accelerator mass spectrometry ) and PET ( Positron emission tomography ) Both of these rely on assessment and analysis of radio isotopes incorporated into the drug under study 25

26. Analytical methods In case of AMS, {14C} is the most useful isotope for drug metabolism studies , whereas for PET {11C} is proving to be the most useful AMS is used for determining PK data by taking body samples over time, processing the sample in the laboratory and then analyzing their drug content PET provides primarily PD data, receptor occupancy data through real-time imaging and some limited PK data 26

27. Advantages 27

28. Beneficiary By incorporating the innovative idea of Phase 0 trials, the main beneficiary will eventually be the patient population at large If the Phase 0 trial study reports identify an Investigational new drug as not being of therapeutic worth , the patient population may certainly be benefited through the minimization of the study participants recruited to subsequent trials on the critical path 28

29. Limitations Absence of therapeutic or diagnostic intent discourages the volunteers to take part in trial Very few biomarkers are available to predict the efficacy of some drugs( anti-cancer drugs), and modulation of bio-marker in such a low dose in 7 days is further a barrier Micro dose not always correctly measures PK/PD behavior of the therapeutic dose of the drug, because at micro dose, most of the compounds dissociate and dissolve rapidly, so fast and extensive absorption and it ( absorption, Cmax, Tmax, AUC ) depends on dissolution 29

30. Limitations Developing radio-isotope for analytical methods like AMS and PET are costly and needs specialized mechanisms, these tracers also have a shorter tracer half life and low specificity ( chance of including metabolites also ) 30

31. Ethical issue No diagnostic and/or therapeutic intent or benefit from Phase 0 trial Risk from research related interventions , for instance repeated tumour biopsies ( in cancer studies ) Proper informed consent process of phase 0 must include : 1- Clear explanation of rationality of the study 2- Proper explanation that this is not therapeutic trial, but experimental 3- Absolutely no anticipated direct clinical benefit 31

32. Phase 1 clinical trial It is the first step in testing (if phase 0 not conducted ) a new intervention in humans that does not benefit human volunteers ( Non-therapeutic trial ) Also known as Human pharmacology and safety study The premise where phase 1 trial is conducted is called as Phase 1 unit 32

33. Phase 1 clinical trial Purpose of Phase 1 clinical trial To determine whether drug is safe to check for its efficacy in Phase 2 trial or not 33

34. Objectives of Phase 1 trial 1- To assess safety of the drug 2- To assess tolerability of the drug 3- To calculate MTD ( Maximum tolerated dose ) of the drug and dose range 4- To evaluate PK ( Pharmacokinetic properties ) and PD ( Pharmacodynamic properties ) of the drug This objectives provide firm basis for investigators to determine further testing of drug on humans ( to decide go- vs non-go- ) 34

35. The Ultimate Goal : 35

36. Pre-requisite Pre-clinical work that establishes the new molecular entity to be safe and tolerable in animal and in vitro models Study population Inclusion criteria : Normal healthy volunteers ( 20-100 participants ), uniformity of subjects about age, sex Exclusion criteria : Women of child bearing age, children Exception : Patients in case of study of toxic investigational chemical entity ( study for anti-cancer drugs ) 36

37. Informed consent Subject who enter phase 1 trial need to be fully informed that these studies usually the initial clinical experiments in human Expected side effects as noted in pre-clinical studies are presented and the possibility of other unpredictable side effects can occur must be stated Preferably be explained by clinical staff at the study site rather than the sponsor and must contain rationale for the start dose and maximum dose in lay language 37

38. Study site, CPUs, Study volunteers : Studies are conducted in clinical trial unit known as CPUs ( Central pharmacological unit ) CPUs are run by CRO ( Contact research organization ), who are conducting clinical trial on behalf of Sponsor/Pharmaceutical company Studies are conducted under supervision of trained Clinical Pharmacologists Study participants receives 24 hr. medical attention and oversight by full time staff Volunteers are paid an inconvenience fees for their time spent and pay depends upon the length of the participation 38

39. Facilities at CPUs required Inpatient stay facility Facilities and personnel for acute emergency coupled with ICU Facilities to monitor all physiological functions and signs Facilities for routine investigation of hematological, biochemical parameters, ECG, X-ray, urine analysis Drug specific biomarker assessment facility 39

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41. Formulations of IND used Intravenous : Most flexible as 1- Dose can be adjusted easily 2- Administration can be stopped immediately if any adverse events occurs Oral : Oral powder reconstituted as suspension or solution is administered to the subject Tablet formulations may be used as well 41

42. Estimation of MRSD ( Maximum recommended safe dose ) Involves 5 steps 1- Determination of NOAEL ( No Observed Adverse Effect Level ) NOAEL - highest dose that does not produce adverse effect Calculated from each species tested 42

43. 2- Conversion of NOAEL to HED HED- Human Equivalent Dose Formula : 43

44. 3- Select most appropriate species Pick one HED for subsequent derivation of the MRSD This HED is chosen from the most appropriate species 4- Apply safety factor After calculating HED of the NOAEL in most appropriate species, Safety factor will be applied, To provide a margin of the safety for the protection of human subjects receiving the initial clinical dose 44

45. Due to 1- Difficulties in detecting certain toxicities in animals 2- Unexpected toxicities 3- Interspecies differences in ADME MRSD in calculated, by dividing the HED by the safety factor In general safety factor of 10 is used to divide HED, but safety factor of 50 should be applied for small molecules 45

46. E.G.- if NOAEL of a drug in mouse model is 15 mg/kg then, HED will be – 15 × 0.08 = 1.2 mg/kg MRSD will be – 1.2/10 = 0.12 mg/kg Alternatives : 1- Micro dosing / Phase 0 study – Using 1/100 th dose 2- MABEL - minimum anticipated biological effect level / MED ( Minimum effective dose ) 46

47. Assessments done in Phase 1 study Pharmacokinetic parameters Evaluation of ADME of drug Most important evaluation is metabolism and clearance to anticipate possibility of accumulation of drug or its metabolite These assist in formulation development and to determine dosage in different age group Study of food effect on bioavailability is also determined here 47

48. Parameters assessed here : 1- Cmax ( maximum plasma concentration achieved ) 2- Tmax ( Time required to reach Cmax ) 3- Vmax ( maximum rate of absorption of the drug ) 4- AUC ( Are under the curve ) 5- Vd ( Volume of distribution of the drug ) 6- t half ( Half life of the drug ) 48

49. Subsequent studies done 1- ADME Study : Objective – to understand the metabolism and full clearance mechanism of the drug and its metabolites in human and to anticipate possibility of the accumulations of the same Information gained – Primary mechanism(s) of elimination of drug from the body Proportion of parent drug converted to metabolites 49

50. 2- Bioavailability/ Bioequivalence ( BA/BE ) Study : Objective – To evaluate the rate and extent of absorption of the drug from a test formulation 3- Food effect study : Objective- To evaluate the effect of food on rate and extent of drug absorption from a given formulation Information gained – Effect of food on the BA of oral drugs and whether to administer drug on empty stomach or without regards to meal 50

51. 4- Renal impairment study : Effect of renal impairment on drug clearance , dosage recommendations for various stages of renal impairment 5- Hepatic impairment study : Effect of hepatic impairment on PK of parent drug and its metabolites Dosage recommendations for the same 51

52. Pharmacodynamic assessment Blood samples are collected and stored Done to identify appropriate and validated biomarker for determination of the drug activity and efficacy Early measurement of drug activity Secondary objective of phase 1 trial If easily measurable parameters ( e.g- BP, FBS ) are available, and if changes occurs with a short duration and low dose of the drug exposure, then drug activity can be assessed earlier 52

53. Assessment of Safety and Tolerability Dose escalation-de-escalation : Rule based design Single ascending study design 53

54. Single dose is given, and effects are observed The assessment is mainly based on DLT (Dose limiting toxicity) If PK data is in line with predicted safety value , then dose is increased in next group of cohort Dose escalation is continued till MTD (Maximum Tolerated Dose ) is defined 54

55. Multiple Ascending Dose design 55

56. Traditional 3+3 design 56

57. MTD- Highest dose of the drug that produce desired therapeutic effect with acceptable, tolerable and predictable adverse effects MTD determination is important objective of Phase 1 study The MTD measured, will be recommended as the starting dose for subsequent study in Phase 2 trial 57

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59. References Maiti Rituparna.2020. Postgraduate Topics in Pharmacology. 3 rd ed. : Paras Medical Books Postgraduate Pharmacology 1 st Edition 2020 by Sougata Sarkar Tripathi, K. D. 2018.  Essentials of Medical Pharmacology . 8th ed. New Delhi, India: Jaypee Brothers Medical. Satoskar, R., Rege, N., & Bhandarkar, S. (2017).  Pharmacology and Pharmacotherapeutics  (25th ed.). New Delhi, India: Elsevier . 59

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