| List of figures |
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xxi | |
| List of tables |
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xxiii | |
| Preface |
|
xxv | |
| Acknowledgments |
|
xxxvii | |
| Introduction |
|
xxxix | |
| Author |
|
xliii | |
| 1 Introduction to biosimilar and interchangeable products |
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1 | (38) |
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1 | (1) |
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2 | (2) |
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4 | (1) |
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European perspective on interchangeability |
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5 | (1) |
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Legality of interchangeability |
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6 | (1) |
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Interchangeability practices |
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7 | (2) |
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9 | (3) |
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12 | (1) |
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12 | (2) |
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14 | (1) |
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Regulatory filing under 505(b)(2) |
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14 | (1) |
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15 | (1) |
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16 | (1) |
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FDA views on development of biosimilars |
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17 | (4) |
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Size and complexity of biological drugs: protein therapeutics |
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18 | (1) |
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Potential benefits of improved analytical methods |
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19 | (1) |
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Potential benefits of new measurement standards |
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20 | (1) |
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Three specific properties needing improved measurement |
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20 | (1) |
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21 | (1) |
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22 | (1) |
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23 | (2) |
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25 | (1) |
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26 | (2) |
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28 | (1) |
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29 | (10) |
| 2 Intellectual property issues for biosimilars |
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39 | (42) |
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Global patenting perspective |
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39 | (7) |
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Comparison of U.S. and European Laws |
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39 | (3) |
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First to file versus first to invent |
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39 | (1) |
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39 | (1) |
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40 | (1) |
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Publication of patent applications |
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40 | (1) |
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Rights conferred by a granted patent |
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40 | (1) |
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40 | (1) |
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41 | (1) |
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42 | (1) |
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42 | (4) |
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46 | (12) |
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Overview of patenting biotechnology |
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47 | (1) |
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Overview of exclusivities for biological products |
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48 | (3) |
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51 | (10) |
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54 | (2) |
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56 | (2) |
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58 | (1) |
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58 | (1) |
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59 | (1) |
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Determination of target launch dates for biologics |
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59 | (1) |
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Loss of patent exclusivity |
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60 | (1) |
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Freedom-to-operate opinions |
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61 | (7) |
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65 | (2) |
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65 | (1) |
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Cabilly's scope of protection |
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66 | (1) |
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67 | (10) |
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68 | (1) |
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68 | (1) |
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Filing the 351(k) triggers the patent dance |
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68 | (5) |
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First patent dance failed |
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73 | (3) |
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Notice of commercial marketing and preliminary injunction |
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76 | (1) |
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77 | (2) |
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Meaning of the 180-day notification language |
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77 | (1) |
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78 | (1) |
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78 | (1) |
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79 | (1) |
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80 | (1) |
| 3 European regulatory guidance |
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81 | (54) |
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81 | (11) |
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84 | (1) |
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84 | (1) |
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85 | (1) |
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85 | (1) |
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85 | (1) |
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86 | (1) |
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86 | (2) |
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88 | (4) |
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88 | (4) |
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Publication of clinical data |
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92 | (3) |
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Arguments in favor of a restricted publication of clinical trial data |
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92 | (1) |
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93 | (5) |
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93 | (2) |
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95 | (3) |
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Product-specific guidance |
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98 | (20) |
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Human follicle stimulating hormone (r-hFSH) |
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98 | (3) |
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99 | (1) |
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99 | (1) |
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99 | (1) |
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100 | (1) |
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101 | (1) |
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101 | (4) |
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102 | (1) |
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102 | (1) |
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102 | (1) |
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103 | (1) |
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104 | (1) |
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105 | (5) |
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107 | (1) |
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108 | (1) |
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108 | (1) |
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108 | (2) |
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110 | (4) |
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110 | (1) |
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110 | (1) |
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PK parameters of interest |
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110 | (1) |
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Timing of the PK evaluation |
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111 | (2) |
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113 | (1) |
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114 | (4) |
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115 | (1) |
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115 | (1) |
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115 | (3) |
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118 | (13) |
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Low-molecular-weight heparins |
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118 | (4) |
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119 | (1) |
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120 | (1) |
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120 | (2) |
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122 | (2) |
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122 | (1) |
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123 | (1) |
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123 | (1) |
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124 | (1) |
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Extrapolation of evidence |
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124 | (1) |
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124 | (2) |
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125 | (1) |
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125 | (1) |
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126 | (1) |
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126 | (3) |
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127 | (1) |
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127 | (1) |
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128 | (1) |
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129 | (14) |
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129 | (1) |
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130 | (1) |
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130 | (1) |
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131 | (1) |
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131 | (4) |
| 4 EMA-approved biosimilars |
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135 | (22) |
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135 | (1) |
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135 | (3) |
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138 | (1) |
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139 | (2) |
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141 | (2) |
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143 | (1) |
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143 | (1) |
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143 | (1) |
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143 | (1) |
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144 | (2) |
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144 | (1) |
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145 | (1) |
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146 | (2) |
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148 | (3) |
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151 | (1) |
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151 | (6) |
| 5 FDA regulatory guidance |
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157 | (70) |
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157 | (1) |
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158 | (1) |
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Nonclinical studies for biologics |
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159 | (5) |
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160 | (1) |
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160 | (1) |
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Typical preclinical testing |
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160 | (1) |
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Clinical studies for biologics |
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161 | (1) |
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Investigational new drug application |
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161 | (1) |
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161 | (1) |
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Manufacturing process changes |
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162 | (1) |
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Meetings with the Food and Drug Administration before and during the clinical trial period |
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163 | (1) |
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Biologics license application |
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164 | (2) |
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Contents of the biologics license application |
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164 | (1) |
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Food and Drug Administration review |
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164 | (2) |
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165 | (1) |
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166 | (11) |
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166 | (4) |
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Reference product exclusivity |
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170 | (1) |
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Biosimilarity versus interchangeability |
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171 | (2) |
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171 | (1) |
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172 | (1) |
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Reference product exclusivity |
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173 | (1) |
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Prelitigation patent-related procedures |
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173 | (1) |
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174 | (1) |
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Confidential access to biological application |
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175 | (1) |
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176 | (1) |
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Declaratory judgment actions |
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176 | (1) |
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176 | (1) |
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177 | (24) |
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179 | (1) |
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179 | (1) |
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Manufacturing process considerations |
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180 | (1) |
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181 | (1) |
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181 | (1) |
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182 | (1) |
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182 | (1) |
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183 | (1) |
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183 | (1) |
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184 | (1) |
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Animal PK and PD measures |
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184 | (1) |
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Animal immunogenicity studies |
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185 | (1) |
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185 | (1) |
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185 | (1) |
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Clinical immunogenicity assessment |
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186 | (2) |
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Clinical safety and effectiveness data |
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188 | (1) |
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Clinical study design issues |
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189 | (2) |
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Extrapolation of clinical data across indications |
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191 | (1) |
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Postmarketing considerations |
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191 | (1) |
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192 | (1) |
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192 | (1) |
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193 | (1) |
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Quantitative evaluation of bioequivalence |
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193 | (1) |
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194 | (1) |
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195 | (1) |
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195 | (1) |
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Criteria, design, and statistical methods for biosimilarity |
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196 | (1) |
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Criteria for biosimilarity |
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196 | (1) |
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196 | (1) |
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197 | (1) |
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197 | (1) |
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Definition and basic concepts |
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197 | (1) |
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Switching and alternating |
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197 | (1) |
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198 | (1) |
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198 | (3) |
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Clinical pharmacology data to support biosimilarity |
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201 | (11) |
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201 | (1) |
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Role of clinical pharmacology studies |
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202 | (1) |
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Critical considerations in the use of clinical pharmacology studies to support biosimilarity |
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203 | (4) |
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Exposure and response assessment to support a demonstration of biosimilarity |
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203 | (1) |
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Evaluation of residual uncertainty |
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204 | (1) |
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Assumptions about analytical quality and similarity |
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204 | (1) |
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Integrity of the bioanalytical methods used in PK and PD studies |
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205 | (1) |
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General PK assay considerations |
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205 | (1) |
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General PK and PD assay considerations |
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205 | (1) |
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Agency guidance for industry bioanalytical method validation |
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206 | (1) |
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Developing clinical pharmacology data for supporting a demonstration of biosimilarity |
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207 | (4) |
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207 | (1) |
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207 | (1) |
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208 | (1) |
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208 | (1) |
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208 | (1) |
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209 | (1) |
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209 | (1) |
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210 | (1) |
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210 | (1) |
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Statistical comparison of PK and PD results |
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211 | (1) |
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Utility of simulation tools in study design and data analysis |
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211 | (1) |
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212 | (2) |
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What are a reference product, biosimilar, and interchangeable product? |
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213 | (1) |
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What is reference product exclusivity? |
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213 | (1) |
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What does the reference product exclusivity expiry date indicate? |
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213 | (1) |
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Why is a determination of the date of first licensure not made for every 351(a) biological product licensed and currently marketed? |
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214 | (1) |
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How often will these lists be updated? |
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214 | (1) |
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What should a healthcare practitioner keep in mind while using these lists? |
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214 | (1) |
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214 | (7) |
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221 | (6) |
| 6 ROW regulatory guidance |
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227 | (112) |
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227 | (5) |
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227 | (1) |
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Reference product considerations |
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228 | (1) |
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Requirements for comparability data |
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229 | (1) |
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Requirements for local studies |
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229 | (2) |
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Recommendations for developing countries |
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231 | (1) |
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232 | (1) |
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232 | (1) |
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233 | (1) |
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233 | (1) |
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Canadian guidelines on subsequent entry biologics (SEBs) |
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234 | (14) |
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234 | (1) |
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234 | (1) |
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234 | (1) |
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235 | (1) |
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235 | (1) |
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Abbreviations and acronyms |
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236 | (1) |
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236 | (1) |
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Guidance for implementation |
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237 | (1) |
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237 | (1) |
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Patents, intellectual property, and data protection |
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237 | (1) |
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237 | (1) |
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Considerations for the use of a non-Canadian reference biologic drug |
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238 | (1) |
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238 | (1) |
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Consultation with Health Canada |
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238 | (1) |
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Information requirements for clinical trial applications (CTA) |
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239 | (1) |
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Information requirements for new drug submissions (NDS) |
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239 | (1) |
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239 | (4) |
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Considerations for the comparability exercise |
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239 | (1) |
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240 | (2) |
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Manufacturing process considerations |
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242 | (1) |
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Determination of similarity |
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243 | (1) |
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243 | (1) |
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Changes following issuance of market authorization |
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243 | (1) |
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Nonclinical and clinical information |
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243 | (3) |
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243 | (1) |
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244 | (1) |
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244 | (2) |
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Risk management plan (RMP) |
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246 | (1) |
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Pharmacovigilance plan (PvP) |
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247 | (1) |
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247 | (1) |
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Adverse drug reaction (ADR) reporting |
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247 | (1) |
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Periodic safety update reports (PSURs) |
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247 | (1) |
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Suspension or revocation of NOfC |
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247 | (1) |
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Labeling requirements (product monograph) |
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247 | (1) |
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Harmonization with other international regulators |
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248 | (1) |
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248 | (8) |
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248 | (1) |
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248 | (1) |
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249 | (1) |
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249 | (1) |
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249 | (1) |
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249 | (2) |
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Biosimilar product approach |
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249 | (1) |
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Choice of reference product |
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250 | (1) |
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251 | (1) |
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251 | (3) |
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251 | (1) |
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Nonclinical documentation |
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252 | (1) |
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252 | (2) |
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Interchangeability and substitutability |
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254 | (1) |
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Pharmacovigilance requirements |
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254 | (1) |
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Reviewing of periodic safety update reports (PSURs) for biosimilar products |
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255 | (1) |
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Risk management plans for biosimilar products |
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255 | (1) |
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255 | (1) |
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255 | (1) |
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Post-approval batch release requirements |
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255 | (1) |
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256 | (12) |
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256 | (1) |
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Chinese guidelines (draft) |
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256 | (1) |
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256 | (1) |
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257 | (1) |
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257 | (1) |
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General guidelines for R&D and evaluation |
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257 | (1) |
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Principle of comparability studies |
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257 | (1) |
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Principle of stepwise development |
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257 | (1) |
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258 | (1) |
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Principle of evaluation on similarity |
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258 | (1) |
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Product quality studies and evaluation |
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258 | (3) |
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258 | (1) |
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258 | (1) |
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258 | (1) |
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259 | (1) |
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260 | (1) |
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260 | (1) |
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260 | (1) |
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Evaluation of CMC similarity |
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260 | (1) |
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Nonclinical studies and evaluation |
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261 | (1) |
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261 | (1) |
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261 | (1) |
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261 | (1) |
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261 | (1) |
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Repeated-dose toxicity studies |
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262 | (1) |
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Other toxicological studies |
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262 | (1) |
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Nonclinical similarity evaluation |
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262 | (1) |
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Clinical studies and evaluation |
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262 | (3) |
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262 | (1) |
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263 | (1) |
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264 | (1) |
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264 | (1) |
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264 | (1) |
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Extrapolation of indications |
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265 | (1) |
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265 | (1) |
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265 | (1) |
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265 | (1) |
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265 | (3) |
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268 | (20) |
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270 | (1) |
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Background and objectives |
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270 | (1) |
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Applicable regulations and guidelines |
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270 | (1) |
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271 | (1) |
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Review Committee on Genetic Manipulation (RCGM) |
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271 | (1) |
|
Genetic Engineering Appraisal Committee (GEAC) |
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271 | (1) |
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Central Drugs Standard Control Organization (CDSCO) |
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271 | (1) |
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271 | (1) |
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Principles for development of similar biologics |
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272 | (5) |
|
Selection of reference biologic |
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273 | (1) |
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273 | (1) |
|
Quality-based considerations for similar biologics |
|
|
274 | (3) |
|
Quality comparability study |
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277 | (1) |
|
Data requirements for preclinical studies |
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|
277 | (4) |
|
Prerequisite before conducting preclinical studies |
|
|
277 | (1) |
|
Preclinical studies (pharmacodynamic and toxicology studies) |
|
|
278 | (2) |
|
Immune responses in animals |
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|
280 | (1) |
|
Data requirements for clinical trial application |
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|
281 | (2) |
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|
281 | (1) |
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282 | (1) |
|
Confirmatory safety and efficacy study |
|
|
282 | (1) |
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Safety and immunogenicity data |
|
|
283 | (1) |
|
Extrapolation of efficacy and safety data to other indications |
|
|
283 | (1) |
|
Data requirements for market authorization application |
|
|
283 | (1) |
|
Post-market data for similar biologics |
|
|
284 | (1) |
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284 | (1) |
|
Adverse drug reaction (ADR) reporting |
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284 | (1) |
|
Post-marketing studies (PMS) |
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284 | (1) |
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285 | (1) |
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|
285 | (3) |
|
Physicochemical and biological characterization of nucleic acid—based recombinant products |
|
|
285 | (1) |
|
Physicochemical and biological characterization of therapeutic proteins |
|
|
286 | (1) |
|
Physicochemical and biological characterization of therapeutic enzymes |
|
|
287 | (1) |
|
Physicochemical and biological characterization of antibodies |
|
|
288 | (1) |
|
Islamic Republic of Iran (National Regulatory Authority) |
|
|
288 | (4) |
|
|
|
289 | (3) |
|
|
|
292 | (12) |
|
Japan biosimilar guidance outline |
|
|
292 | (1) |
|
Guideline for the quality, safety, and efficacy of follow-on biological medicinal products |
|
|
293 | (15) |
|
|
|
293 | (1) |
|
|
|
293 | (1) |
|
General principles for the development of follow-on biological medicinal products |
|
|
294 | (1) |
|
Manufacturing process and characterization of a FOBMP |
|
|
295 | (2) |
|
Comparability exercise in terms of quality attributes |
|
|
297 | (1) |
|
Comparative study on structural analysis and physicochemical property |
|
|
298 | (1) |
|
Specifications and test procedures |
|
|
299 | (1) |
|
|
|
299 | (1) |
|
|
|
300 | (2) |
|
Post-marketing surveillance |
|
|
302 | (1) |
|
|
|
303 | (1) |
|
Jordan Food and Drug Administration |
|
|
304 | (1) |
|
|
|
304 | (1) |
|
|
|
305 | (1) |
|
|
|
306 | (1) |
|
|
|
307 | (1) |
|
|
|
307 | (1) |
|
World Health Organization (WHO) |
|
|
308 | (25) |
|
|
|
308 | (1) |
|
|
|
308 | (3) |
|
|
|
311 | (1) |
|
|
|
312 | (1) |
|
|
|
312 | (1) |
|
|
|
312 | (1) |
|
Scientific considerations and concept for licensing SBPs |
|
|
313 | (1) |
|
|
|
314 | (1) |
|
Key principles for the licensing of SBPs |
|
|
314 | (1) |
|
Reference biotherapeutic products (RBPs) |
|
|
315 | (1) |
|
Considerations for choice of RBP |
|
|
315 | (1) |
|
|
|
316 | (5) |
|
|
|
317 | (1) |
|
|
|
318 | (2) |
|
|
|
320 | (1) |
|
|
|
320 | (1) |
|
|
|
321 | (1) |
|
|
|
321 | (3) |
|
|
|
321 | (1) |
|
|
|
322 | (2) |
|
|
|
324 | (8) |
|
|
|
324 | (1) |
|
|
|
325 | (1) |
|
Confirmatory pharmacokinetic/pharmacodynamic studies |
|
|
326 | (1) |
|
|
|
326 | (3) |
|
|
|
329 | (1) |
|
|
|
330 | (1) |
|
Extrapolation of efficacy and safety data to other clinical indications |
|
|
331 | (1) |
|
|
|
332 | (1) |
|
Prescribing information and label |
|
|
332 | (1) |
|
Roles and responsibilities of national regulatory authorities |
|
|
333 | (1) |
|
|
|
333 | (6) |
| 7 U.S. commercialization |
|
339 | (32) |
|
|
|
339 | (2) |
|
|
|
341 | (1) |
|
|
|
342 | (1) |
|
|
|
342 | (1) |
|
Shift from small molecule to specialty drugs |
|
|
343 | (1) |
|
Biosimilar opportunity 2013-2020 |
|
|
343 | (1) |
|
|
|
343 | (17) |
|
Industry structure summary |
|
|
343 | (1) |
|
|
|
344 | (6) |
|
|
|
350 | (1) |
|
|
|
350 | (2) |
|
|
|
351 | (1) |
|
Controlling acquisition cost |
|
|
352 | (2) |
|
|
|
352 | (1) |
|
|
|
353 | (1) |
|
|
|
353 | (1) |
|
|
|
353 | (1) |
|
|
|
354 | (3) |
|
|
|
354 | (1) |
|
|
|
355 | (1) |
|
|
|
356 | (1) |
|
|
|
356 | (1) |
|
|
|
357 | (3) |
|
|
|
357 | (1) |
|
|
|
358 | (1) |
|
|
|
358 | (1) |
|
|
|
358 | (1) |
|
|
|
358 | (2) |
|
|
|
360 | (1) |
|
Commercializing a biosimilar |
|
|
360 | (5) |
|
|
|
361 | (1) |
|
|
|
361 | (2) |
|
|
|
363 | (1) |
|
|
|
364 | (1) |
|
|
|
365 | (1) |
|
Industry events and forums |
|
|
365 | (1) |
|
|
|
365 | (1) |
|
|
|
366 | (1) |
|
|
|
366 | (1) |
|
|
|
366 | (3) |
|
|
|
366 | (1) |
|
|
|
367 | (4) |
|
Medical science liaison support |
|
|
367 | (1) |
|
Pharmacovigilance (drug safety) |
|
|
367 | (1) |
|
Adverse event identification/reporting process |
|
|
368 | (1) |
|
Product complaint reporting/crisis management |
|
|
369 | (1) |
|
|
|
369 | (2) |
| 8 Global commercialization |
|
371 | (16) |
|
|
|
371 | (3) |
|
|
|
371 | (3) |
|
|
|
374 | (11) |
|
|
|
379 | (1) |
|
|
|
379 | (1) |
|
|
|
379 | (5) |
|
|
|
384 | (1) |
|
|
|
385 | (2) |
| 9 Quality and lifecycle management |
|
387 | (100) |
|
|
|
387 | (1) |
|
Pharmaceutical development |
|
|
387 | (6) |
|
|
|
389 | (1) |
|
|
|
389 | (1) |
|
|
|
389 | (2) |
|
|
|
391 | (2) |
|
Critical quality attributes |
|
|
393 | (2) |
|
|
|
393 | (1) |
|
|
|
393 | (1) |
|
|
|
394 | (1) |
|
Product life cycle management and continual improvement |
|
|
395 | (1) |
|
Quality risk management and product and process development |
|
|
395 | (1) |
|
Differing approaches to pharmaceutical development |
|
|
396 | (1) |
|
CMC considerations for the drug substance |
|
|
396 | (4) |
|
CMC considerations for the drug product |
|
|
400 | (3) |
|
|
|
403 | (2) |
|
FDA comparability protocol (CP) |
|
|
405 | (13) |
|
|
|
405 | (1) |
|
|
|
406 | (2) |
|
|
|
407 | (1) |
|
|
|
407 | (1) |
|
When and why were CPs created? |
|
|
407 | (1) |
|
Information on PAC and assessment of CP |
|
|
407 | (1) |
|
|
|
408 | (2) |
|
Reporting of CMC changes? |
|
|
408 | (1) |
|
|
|
408 | (1) |
|
|
|
409 | (1) |
|
|
|
410 | (2) |
|
|
|
410 | (1) |
|
Submission of changes and study results after a CP is approved |
|
|
410 | (1) |
|
Studies not meeting the criteria in the approved CP |
|
|
411 | (1) |
|
|
|
411 | (1) |
|
Modification of an approved CP |
|
|
412 | (1) |
|
|
|
412 | (7) |
|
|
|
412 | (3) |
|
Changes in the manufacturing process |
|
|
415 | (1) |
|
Changes in analytical procedures |
|
|
416 | (1) |
|
Changes in manufacturing equipment |
|
|
416 | (1) |
|
Changes in manufacturing facilities |
|
|
416 | (1) |
|
Container closure system changes |
|
|
417 | (1) |
|
Implementation of or changes in process analytical technology (PAT) |
|
|
417 | (1) |
|
|
|
417 | (1) |
|
|
|
418 | (1) |
|
|
|
418 | (1) |
|
|
|
418 | (1) |
|
Components of a CP submission |
|
|
419 | (3) |
|
|
|
420 | (1) |
|
|
|
420 | (1) |
|
|
|
420 | (1) |
|
|
|
421 | (1) |
|
|
|
421 | (1) |
|
Reporting of the manufacturing change(s) implemented using an approved CP |
|
|
422 | (1) |
|
Comparability of biotechnological/biological products subject to changes in their manufacturing process (Q5e) |
|
|
422 | (9) |
|
|
|
422 | (2) |
|
|
|
422 | (1) |
|
|
|
423 | (1) |
|
|
|
423 | (1) |
|
|
|
424 | (7) |
|
Considerations for the comparability exercise |
|
|
424 | (1) |
|
|
|
425 | (3) |
|
Manufacturing process considerations |
|
|
428 | (1) |
|
Demonstration of comparability during development |
|
|
429 | (1) |
|
Nonclinical and clinical considerations |
|
|
430 | (1) |
|
|
|
431 | (14) |
|
Quality assurance systems |
|
|
431 | (1) |
|
|
|
432 | (1) |
|
Identification and clearance methods for impurities |
|
|
433 | (2) |
|
|
|
435 | (1) |
|
|
|
435 | (1) |
|
|
|
436 | (1) |
|
|
|
437 | (1) |
|
|
|
437 | (4) |
|
|
|
441 | (3) |
|
Cell substrates and animals |
|
|
441 | (1) |
|
|
|
441 | (1) |
|
Virus inactivation and removal |
|
|
441 | (3) |
|
|
|
444 | (1) |
|
Analytical method validation |
|
|
444 | (1) |
|
|
|
445 | (26) |
|
|
|
445 | (3) |
|
|
|
446 | (2) |
|
|
|
448 | (1) |
|
|
|
449 | (1) |
|
|
|
450 | (21) |
|
|
|
452 | (1) |
|
|
|
452 | (7) |
|
|
|
459 | (1) |
|
|
|
459 | (1) |
|
|
|
460 | (1) |
|
|
|
461 | (1) |
|
|
|
461 | (1) |
|
Capillary electrophoresis |
|
|
462 | (1) |
|
High performance reversed phase chromatography |
|
|
463 | (1) |
|
High performance size exclusion chromatography |
|
|
463 | (1) |
|
|
|
464 | (2) |
|
Limulus amebocyte lysate assay |
|
|
466 | (1) |
|
|
|
467 | (1) |
|
|
|
467 | (2) |
|
|
|
469 | (1) |
|
|
|
470 | (1) |
|
|
|
471 | (16) |
| Appendix A: A brief history of biosimilars |
|
487 | (4) |
| Appendix B: Patent expiry dates for potential biosimilar products |
|
491 | (18) |
| Appendix C: Biological products licensed in the United States |
|
509 | (74) |
| Index |
|
583 | |
