Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic

Supplementary Online Content

Downing NS, Aminawung JA, Shah ND, Krumholz HM, Ross JS. Clinical trial evidence

supporting fda approval of novel therapeutic agents, 2005-2012. JAMA.

doi:10.1001/jama.2013.282034

eAppendix 1. Additional Information Pertaining to Sample Construction of Novel

Therapeutic Agents Approved by the US Food and Drug Administration Between 2005 and

2012

eAppendix 2. Additional Information Pertaining to Categorization of Novel Therapeutic

Indications Approved by the US Food and Drug Administration Between 2005 and 2012 by

Expected Length of Treatment

eAppendix 3. Additional Information Pertaining to Characterization of Pivotal Trials Used in

the US Food and Drug Administration’s Approvals of Novel Therapeutic Agents Between

2005 and 2012

This supplementary material was provided by the authors to give readers additional

information about their work.

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eAPPENDIX 1. Additional Information Pertaining to Sample Construction of Novel Therapeutic

Agents Approved by the US Food and Drug Administration Between 2005 and 2012

Descriptions of drugs not considered new molecular entities or novel biologics:

• Reformulations of previously approved therapeutics

• Combinations of previously approved therapeutics (n.b., combination therapies including

least one novel therapeutic were not excluded, even if the combination also included

several previously approved therapeutics)

• Vaccines

• Blood products (e.g., clotting factors, immunoglobulins)

• Generic drugs (including biosimilars)

• Over-the-counter drugs

• Veterinary drugs

Level 2 ATC codes describing diagnostic and contrast agents:

• V04 – diagnostic agents

• V08 – contrast media

• V09 – diagnostic radiopharmaceuticals

• Other imaging agents, such as those used in cardiac stress tests

Downloaded From: https://jamanetwork.com/ on 09/25/2021 eAPPENDIX 2. Additional Information Pertaining to Categorization of Novel Therapeutic

Indications Approved by the US Food and Drug Administration Between 2005 and 2012 by

Expected Length of Treatment

Using clinical experience and judgment, members of the study team (NSD, NDS, JSR)

categorized each indication for all novel therapeutics in our sample by expected length of

treatment as acute, intermediate, or chronic.

Definitions:

• Acute treatment was defined as expected use of less than one month

• Intermediate treatment was defined as expected use of one month to two years

o All cancer therapies were classified as intermediate because prognosis is generally poor and the same treatment regimen is rarely used for more than two

years as surviving patients typically rotate between various chemotherapies.

• Chronic treatment was defined as expected use of two years or longer

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Classifications of approved indications by expected length of treatment are shown on the

following pages (n.b., excludes those without a pivotal efficacy trial)

Expected length of INN name Approved indication treatment Vigabatrin Indication 1: Seizures Chronic Avobenzone; Ecamsule; Indication 1: Sunscreen Acute Octocrylene Anidulafungin Indication 1: Candidemia Acute Anidulafungin Indication 2: Esophageal Candidiasis Acute Tipranavir Indication 1: Human Immunodeficiency Virus Chronic Nepafenac Indication 1: Eye pain Acute Deferasirox Indication 1: Iron overload Chronic Sinecatechins Indication 1: Warts Acute Lubiprostone Indication 1: Irritable Bowel Syndrome Chronic Darunavir Ethanolate Indication 1: Human Immunodeficiency Virus Chronic Dasatinib Indication 1: Chronic Myeloid Leukemia Intermediate Sitagliptin Phosphate Indication 1: Type 2 Diabetes Mellitus Chronic Paliperidone Indication 1: Schizophrenia Chronic Telbivudine Indication 1: Hepatitis B Virus Chronic Temsirolimus Indication 1: Renal Cell Carcinoma Intermediate Maraviroc Indication 1: Human Immunodeficiency Virus Chronic Raltegravir Potassium Indication 1: Human Immunodeficiency Virus Chronic Difluprednate Indication 1: Ocular Pain Acute Fospropofol Disodium Indication 1: Anesthesia Acute Bendamustine Hydrochloride Indication 1: Chronic Lymphocytic Leukemia Intermediate Tolvaptan Indication 1: Hyponatremia Acute Eltrombopag Olamine Indication 1: Thrombocytopenia in Idiopathic Chronic Thrombocytopenic Purpura Prasugrel Hydrochloride Indication 1: Platelet inhibitor for patients Chronic status post myocardial infarction, or with angina Besifloxacin Hydrochloride Indication 1: Bacterial conjunctivitis Acute Saxagliptin Hydrochloride Indication 1: Type 2 Diabetes Mellitus Chronic Pitavastatin Calcium Indication 1: Hyperlipidemia Chronic Romidepsin Indication 1: Cutaneous T-Cell Lymphoma Intermediate Vandetanib Indication 1: Medullary Thyroid Cancer Intermediate Pralatrexate Indication 1: Cutaneous T-Cell Lymphoma Intermediate Ulipristal Acetate Indication 1: Contraception Chronic Roflumilast Indication 1: Chronic Obstructive Pulmonary Chronic Disease Fingolimod Indication 1: Multiple Sclerosis Chronic Carglumic Acid Indication 1: N-Acetylglutamate Synthase Chronic Deficiency Abatacept Indication 1: Rheumatoid Arthritis Chronic Alglucosidase Alfa Indication 1: Pompe Disease Chronic Methoxy Polyethylene Glycol- Indication 1: Anemia (secondary to chronic Chronic Epoetin Beta kidney disease) Eculizumab Indication 1: Paroxysmal nocturnal Chronic hemoglobinuria Romiplostim Indication 1: Thrombocytopenia in Idiopathic Chronic Thrombocytopenic Purpura Abobotulinumtoxina Indication 1: Glabellar Lines Intermediate Abobotulinumtoxina Indication 2: Cervical Dystonia Intermediate Ecallantide Indication 1: Hereditary Angioedema Acute Belatacept Indication 1: Organ rejection Intermediate Ofatumumab Indication 1: Chronic Lymphocytic Leukemia Intermediate

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Incobotulinumtoxina Indication 1: Bleopharospasm Intermediate Incobotulinumtoxina Indication 2: Cervical Dystonia Intermediate Ipilimumab Indication 1: Melanoma Intermediate Ceftaroline Fosamil Indication 1: Skin Infections Acute Ceftaroline Fosamil Indication 2: Pneumonia Acute Azilsartan Medoxomil Indication 1: Hypertension Chronic Rilpivirine Hydrochloride Indication 1: Human Immunodeficiency Virus Chronic Abiraterone Acetate Indication 1: Prostate Cancer Intermediate Decitabine Indication 1: Myelodysplastic Syndrome Intermediate Tigecycline Indication 1: Skin Infections Acute Tigecycline Indication 2: Intraabdominal infections Acute Aliskiren Hemifumarate Indication 1: Hypertension Chronic Alcaftadine Indication 1: Allergic conjunctivitis Chronic Lacosamide Indication 1: Seizures Chronic Spinosad Indication 1: Lice Acute Tesamorelin Acetate Indication 1: Human Immunodeficiency Chronic Virus-related lipodystrophy Vilazodone Hydrochloride Indication 1: Depression Chronic Velaglucerase Alfa Indication 1: Gaucher Disease Chronic Telaprevir Indication 1: Hepatitis C Virus Chronic Ramelteon Indication 1: Insomnia (onset) Intermediate Icatibant Acetate Indication 1: Hereditary Angioedema Acute Rivaroxaban Indication 1: Anticoagulation for patients with Intermediate atrial fibrillation Brentuximab Vedotin Indication 1: Hodgkin Lymphoma Intermediate Brentuximab Vedotin Indication 1: Large Cell Lymphoma Intermediate Clobazam Indication 1: Lennox-Gastaut Syndrome Chronic Crizotinib Indication 1: Lung Cancer Intermediate Liraglutide Recombinant Indication 1: Type 2 Diabetes Mellitus Chronic Ezogabine Indication 1: Partial Seizures Chronic Dronedarone Hydrochloride Indication 1: Antiarrhythmic for patients with Chronic atrial fibrillation Pazopanib Hydrochloride Indication 1: Renal Cell Carcinoma Intermediate Dabigatran Etexilate Mesylate Indication 1: Prevention Stroke and Chronic Pulmonary Embolism for patients with atrial fibrillation Bismuth Subcitrate Potassium; Indication 1: Helicobacter Pylori Infection Acute Metronidazole; Tetracycline Galsulfase Indication 1: Mucopolysaccharidosis VI Chronic Panitumumab Indication 1: Colorectal Cancer Intermediate Ranibizumab Indication 1: Wet Age-related Macular Chronic Degeneration Certolizumab Pegol Indication 1: Crohn's Disease Chronic Ustekinumab Indication 1: Plaque Psoriasis Chronic Tocilizumab Indication 1: Rheumatoid Arthritis Chronic Golimumab Indication 1: Rheumatoid Arthritis Chronic Golimumab Indication 2: Psoriatic Arthritis Chronic Golimumab Indication 3: Ankylosing Spondylitis Chronic Pegloticase Indication 1: Gout Chronic Canakinumab Indication 1: Muckle-Wells Syndrome Chronic Cabazitaxel Indication 1: Prostate Cancer Intermediate Eribulin Mesylate Indication 1: Breast Cancer Intermediate Boceprevir Indication 1: Hepatitis C Virus Chronic Micafungin Sodium Indication 1: Esophageal Candidiasis Chronic Micafungin Sodium Indication 2: Hematopoietic Stem Cell Chronic Transplantation prophylaxis against Candida Infection Ranolazine Indication 1: Angina Chronic Conivaptan Hydrochloride Indication 1: Hyponatremia Acute Nebivolol Hydrochloride Indication 1: Hypertension Chronic

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Mecasermin Recombinant Indication 1: Growth Failure Chronic Tetrabenazine Indication 1: Huntington's Disease Chronic Varenicline Tartrate Indication 1: Smoking Cessation Intermediate Methylnaltrexone Bromide Indication 1: Constipation secondary to Acute opioid use Telavancin Hydrochloride Indication 1: Skin Infections Acute Artemether; Lumefantrine Indication 1: Malaria Acute Gabapentin Enacarbil Indication 1: Restless Leg Syndrome Chronic Everolimus Indication 1: Renal Cell Carcinoma Intermediate Idursulfase Indication 1: Hunter Syndrome Chronic Rilonacept Indication 1: Familial Cold Autoinflammatory Chronic Syndrome Denosumab Indication 1: Osteoporosis Chronic Collagenase Clostridium Indication 1: Dupuytren's Contracture Acute Histolyticum Belimumab Indication 1: Systemic Lupus Erythematosus Chronic Lurasidone Hydrochloride Indication 1: Schizophrenia Chronic Linagliptin Indication 1: Type 2 Diabetes Mellitus Chronic Fidaxomicin Indication 1: Clostridium Difficile Infection Acute Pramlintide Acetate Indication 1: Type 2 Diabetes Mellitus Chronic Pramlintide Acetate Indication 2: Type 1 Diabetes Mellitus Chronic Indacaterol Maleate Indication 1: Chronic Obstructive Pulmonary Chronic Disease Ticagrelor Indication 1: Platelet Inhibitor for patients Chronic status post myocardial infarction, or with angina Asparaginase Erwinia Indication 1: Acute Lymphoblastic Leukemia Intermediate Chrysanthemi Aflibercept Indication 1: Wet Age-related Macular Intermediate Degeneration Ruxolitinib Phosphate Indication 1: Myelofibrosis Chronic Vemurafenib Indication 1: Melanoma Intermediate Polidocanol Indication 1: Varicose Veins Acute Insulin Detemir Recombinant Indication 1: Type 1 Diabetes Mellitus Chronic Insulin Detemir Recombinant Indication 2: Type 2 Diabetes Mellitus Chronic Rasagiline Mesylate Indication 1: Parkinson's Disease Chronic Exenatide Synthetic Indication 1: Type 2 Diabetes Mellitus Chronic Alvimopan Indication 1: Gastrointestinal Tract Recovery Acute status post surgery Entecavir Indication 1: Hepatitis B Virus Chronic Rotigotine Indication 1: Parkinson's Disease Chronic Febuxostat Indication 1: Gout Chronic Nelarabine Indication 1: Relapsed T-Cell Acute Intermediate Lymphoblastic Leukemia or Lymphoblastic Lymphoma Lenalidomide Indication 1: Myelodysplastic Syndrome Intermediate Mecasermin Rinfabate Indication 1: Growth Failure Chronic Recombinant Rufinamide Indication 1: Lennox-Gastaut Seizures Chronic Sorafenib Tosylate Indication 1: Renal Cell Carcinoma Intermediate Sunitinib Malate Indication 1: Gastrointestinal Stromal Tumor Intermediate Sunitinib Malate Indication 2: Renal Cell Carcinoma Intermediate Lisdexamfetamine Dimesylate Indication 1: Attention Deficit Hyperactivity Chronic Disorder Vorinostat Indication 1: Cutaneous T-Cell Lymphoma Intermediate Desvenlafaxine Succinate Indication 1: Depression Chronic Posaconazole Indication 1: Fungal Infections Chronic Ciclesonide Indication 1: Allergies Chronic Fesoterodine Fumarate Indication 1: Overactive Bladder Chronic Retapamulin Indication 1: Impetigo Acute

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Lapatinib Ditosylate Indication 1: Breast Cancer Intermediate Ixabepilone Indication 1: Breast Cancer Intermediate Nilotinib Hydrochloride Indication 1: Chronic Myeloid Leukemia Intermediate Monohydrate Lanreotide Acetate Indication 1: Acromegaly Chronic Ambrisentan Indication 1: Pulmonary Hypertension Chronic Doripenem Indication 1: Intra-abdominal Infection Acute Doripenem Indication 2: Urinary Tract Infection Acute Asenapine Maleate Indication 1: Schizophrenia Intermediate Asenapine Maleate Indication 2: Bipolar Disorder Intermediate Benzyl Alcohol Indication 1: Lice infection Acute Clevidipine Butyrate Indication 1: Intra-operative Blood Pressure Acute Control Sapropterin Dihydrochloride Indication 1: Phenylketonuria Chronic Etravirine Indication 1: Human Immunodeficiency Virus Chronic Iloperidone Indication 1: Schizophrenia Intermediate Degarelix Acetate Indication 1: Prostate Cancer Intermediate Silodosin Indication 1: Benign Prostatic Hyperplasia Chronic Dalfampridine Indication 1: Multiple Sclerosis Chronic Dienogest; Estradiol Valerate Indication 1: Contraception Chronic Dienogest; Estradiol Valerate Indication 2: Dysfunctional uterine bleeding Chronic Milnacipran Hydrochloride Indication 1: Fibromyalgia Chronic Bepotastine Besilate Indication 1: Allergies Intermediate Tapentadol Hydrochloride Indication 1: Pain Intermediate Plerixafor Indication 1: Mobilization of Hematopoietic Intermediate Stem Cells in Lymphoma and Multiple Myeloma Ocriplasmin Indication 1: Symptomatic Vitreomacular Acute Adhesion Pasireotide Diaspartate Indication 1: Cushing's Disease Chronic Crofelemer Indication 1: Diarrhea in HIV patients on anti- Chronic retroviral therapy Tafluprost Indication 1: Open Angle Glaucoma / Ocular Chronic Hypertension Mirabegron Indication 1: Overactive Bladder Chronic Carfilzomib Indication 1: Multiple Myeloma Intermediate Linaclotide Indication 1: Chronic Idiopathic Constipation Chronic Linaclotide Indication 2: Irritable Bowel Syndrome with Chronic Constipation Perampanel Indication 1: Partial Seizures Chronic Teriflunomide Indication 1: Relapsing Multiple Sclerosis Chronic Regorafenib Indication 1: Metastatic Colorectal Cancer Intermediate Cobicistat; Elvitegravir; Indication 1: Human Immunodeficiency Virus Chronic Emtricitabine; Tenofovir Disoproxil Fumarate Tofacitinib Citrate Indication 1: Rheumatoid Arthritis Chronic Bosutinib Monohydrate Indication 1: Chronic Myeloid Leukemia Intermediate Vismodegib Indication 1: Basal Cell Carcinoma Intermediate Cabozantinib S-Malate Indication 1: Medullary Thyroid Cancer Intermediate Lomitapide Mesylate Indication 1: Homozygous Familial Chronic Hypercholesterolemia Lucinactant Indication 1: Respiratory Distress Syndrome Acute Taliglucerase Alfa Indication 1: Gaucher Disease Chronic Lorcaserin Hydrochloride Indication 1: Weight Loss Chronic Tbo-Filgrastim Indication 1: Neutropenia Acute Pertuzumab Indication 1: Breast Cancer Intermediate Ziv-Aflibercept Indication 1: Metastatic Colorectal Cancer Intermediate Apixaban Indication 1: Prevention of stroke Chronic Avanafil Indication 1: Erectile Dysfunction Chronic Axitinib Indication 1: Renal Cell Carcinoma Intermediate

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Aclidinium Bromide Indication 1: Chronic Obstructive Pulmonary Chronic Disease Citric Acid; Magnesium Oxide; Indication 1: Colonoscopy Preparation Acute Sodium Picosulfate Peginesatide Acetate Indication 1: Anemia (secondary to chronic Chronic kidney disease) Ingenol Mebutate Indication 1: Actinic Keratosis on face and Acute scalp Ingenol Mebutate Indication 2: Actinic Keratosis on trunk and Acute extremities Ivacaftor Indication 1: Chronic Obstructive Pulmonary Chronic Disease Enzalutamide Indication 1: Metastatic Prostate Cancer Intermediate Teduglutide Recombinant Indication 1: Short-Bowel Syndrome patients Chronic on Parenteral Nutrition Ponatinib Hydrochloride Indication 1: Philadelphia Chromosome Intermediate Positive Hematologic Malignancies Omacetaxine Mepesuccinate Indication 1: Chronic Myeloid Leukemia Intermediate Bedaquiline Fumarate Indication 1: Multi-drug Resistant Intermediate Tuberculosis

Downloaded From: https://jamanetwork.com/ on 09/25/2021

APPENDIX 3. Additional Information Pertaining to Characterization of Pivotal Trials Used in the

US Food and Drug Administration’s Approvals of Novel Therapeutic Agents Between 2005 and

2012

Information typically found in the “Sources of Clinical Data” (section 5) or “Review of

Efficacy” (section 6) components of FDA Medical Review

Randomization: Trials were classified as “randomized” if the medical review specified that

subjects were randomized between arms. All other trials were classified as “non-randomized”

Blinding: Trials were classified according to the level of blinding used.

• “Double-blinded”: Trials that were described in the medical review as “double-blinded”

or blinded to both investigator and patient

• “Single-blinded”: Trials that were described by the medical review as “single-blinded” or

blinded to the patient only

• “No blinding”: Unblinded or “open-label” trials

• “n/a (single arm trial)”: Single arm trials were not classified at all because blinding is not

possible in such a trial design.

Comparator: Trials were classified according to the type of comparator used to evaluate the

study drug:

• “No comparator”: Single arm trials and multi-arm trials comparing the study drug to itself

only

• “Placebo”: Trials comparing the study drug to placebo

Downloaded From: https://jamanetwork.com/ on 09/25/2021 • “Active”: Trials comparing the study drug to another drug (n.b., trials comparing the study

drug to both an active comparator and placebo were included in this classification, even

if the medical review focused on the comparisons of the investigational drug with

placebo).

Primary endpoint: The primary endpoint used to assess the efficacy of the study drug was

classified as “clinical outcome”, “clinical scale”, “surrogate outcome”. Several examples of

primary endpoints for each category are listed below:

• “Clinical outcome”

o Overall survival

o Incidence of stroke or systemic embolism

o Time from randomization to first cardiovascular event

o Rate of chronic obstructive pulmonary disease exacerbation

o Seizure frequency

• “Clinical scale”

o Decrease of greater than 100 in Crohn’s Disease Activity Index

o American College of Rheumatology 20% improvement criteria

o Change from baseline in Montgomery–Åsberg Depression Rating Scale • “Surrogate outcome”

o Uric acid < 6mg/dl ≥ 80% of the study period

o Sustained virologic response defined as undetectable Hepatitis C virus ribonucleic acid 24 weeks after therapy

o Change from baseline in sitting diastolic blood pressure

o Change in mean hemoglobin A1c

o Trough forced expiratory volume in one second 24 hours after dose

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Composite endpoints were classified according to the component which generated the most

patient-important information. For example, a composite endpoint of overall survival, a clinical

outcome, and progression-free survival, a surrogate outcome, would be classified as clinical

outcome. A list of all unique primary endpoints and their classifications is provided below.

Primary endpoint Classification 1. 5% weight losers, AND 2. 10% weight losers, AND 3. weight loss Clinical 1. Abdominal pain, AND 2. Complete spontaneous bowel movements Clinical 1. Absence of systemic fungal infection at end of treatment AND 2. Absence of systemic Clinical fungal infection at 4 week follow-up visit 1. Change in 6 minute walk test from baseline, AND 2. Change in forced vital capacity Clinical 1. Change in International Index of Erection Function domain score from baseline to end of treatment, AND 2. Change in percentage of sexual attempts resulting in successful vaginal Clinical penetration, AND 3. Change in percentage of sexual attempts resulting in successful intercourse 1. Change in post-bronchodilator forced expiratory volume in one second, AND 2. Rate of Clinical chronic obstructive pulmonary disease exacerbation 1. Change in pre-bronchodilator forced expiratory volume in one second, AND 2. Change Clinical in rate of chronic obstructive pulmonary disease exacerbation 1. Cardiovascular death, OR 2. Non-fatal myocardial infarction, OR 3. Stroke Clinical 1. Death from vascular causes, OR 2. Myocardial infarction, OR 3. Stroke Clinical 1. Death, OR 2. Any deep vein thrombosis, OR 3. Non-fatal pulmonary embolism Clinical 1. Incidence of respiratory distress syndrome at 24 hours, AND 2. Respiratory distress Clinical syndrome-related mortality at 14 days 1. Overall response rate (complete + partial response), AND 2. Time to acute myeloid Clinical leukemia OR death 1. Overall survival, AND 2. Progression free survival Clinical 1. Patient and graft survival at 12 months, AND 2. Renal impairment Clinical 1. Patient and graft survival at 12 months, AND 2. Renal impairment, AND 3. acute Clinical rejection by histology 1. Proportion of patients with laxation response within 4 hour of FIRST dose study drug (i.e., day 1), AND 2. Proportion of patients who had laxation response within 4 hours after Clinical at least 2 of first 4 doses (i.e., in first week of trial) 1. Stroke, AND 2. Non-central nervous system embolism Clinical 1. Weight loss at 52 weeks, AND 2. Maintain loss at 104 weeks Clinical 4-hour laxation response on day 1 Clinical 4-week continuous quit rate from weeks 9-12 (i.e., total abstinence in this period - Clinical measured end expiratory exhaled carbon monoxide) Absence of dysfunctional uterine bleeding symptoms Clinical Annualized relapse rate at 24 months Clinical Average number of weekly angina attacks Clinical Average subjective sleep latency Clinical Average number of urinary frequency and urge incontinence events per 24 hours Clinical Change from baseline in 6 min walking distance Clinical Change in height velocity Clinical Change in partial seizure frequency Clinical Change in the mean total daily 'OFF' time baseline from patient diaries Clinical Clinical cure rate at test-of cure visit (8-15 days s/p last dose) Clinical Clinical resolution and eradication of baseline bacterial infection Clinical Clinical response at test-of-cure visit (days 7-14) (Resolution of S&S of skin/soft tissue Clinical infection such that no further treatment needed) Clinical response/diarrhea symptoms based on patient diary Clinical Complete clearance rate (i.e., no clinically visible actinic keratosis) Clinical

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Complete spontaneous bowel movement overall responder Clinical Complete visual clearance of all warts Clinical Continuous abstinence from weeks 13-24 (measured with end-expiratory carbon monoxide Clinical testing) Cure rate ("Subjects, who in the opinion of the investigator, required no further Clostridium Difficile-associated diarrhea therapy 2 days after the completion of study medication were Clinical considered cure. Subjects who had three of fewer unformed stools in two consecutive days were considered cured") Distance walked in 12 minute walk test Clinical Endoscopic cure at end of therapy Clinical Endoscopic response at end of therapy Clinical Global response (1. clinical cure or improvement (i.e., in symptoms) AND 2. negative Clinical candida cultures x 2) Incidence of stroke and systemic embolism Clinical Laxation within 4 hours of dose Clinical Mean change from baseline in urination/incontinence episodes per 24 hours Clinical Number of pregnancies Clinical Overall survival Clinical Per patient clinical response (cure) at test of cure visit (8-15 days after last dose) Clinical Percent change in total partial seizure frequency over 28 day period from baseline Clinical Percent of treatment failure (composite of ocular pain, aqueous cell score OR aqueous Clinical flare score) Percent reduction in the number of drop seizures (4 week baseline vs. treatment period) Clinical Pregnancy rate Clinical Presence of live lice Clinical Proportion of lice free households 2 weeks after last treatment Clinical Proportion of patients that are alive and free of ventilator support at 18 months of age Clinical Proportion of subjects who had a reduction of 20%-100% in parenteral nutrition volume at Clinical week 20, 24 compared to baseline Proportion of patients with contracture reduction of primary proximal Clinical interphalangeal/metacarpophalangeal joint to 0-5 degrees within 30 days of last injection Rate of spontaneous bowel movements Clinical Seizure frequency Clinical Successful prophylaxis of (proven or provable) invasive fungal infection Clinical Successful sedation (1. Modified Observer's Assessment of Alertness/Sedation score, AND Clinical 2. Completion of procedure without alternate sedation or manual/mechanical ventilation) Time from randomization to first cardiovascular hospitalization or death Clinical Timed 25 foot walk walking speed (for multiple sclerosis patients) Clinical Weight loss at 52 weeks Clinical Percent of subjects who lost less than 15 letters in the corrected visual acuity score at 12 Scale months 1. 20% improvement in American College of Rheumatology score at 6 months, AND 2. Health Assessment Questionnaire Disability Index greater than 0.3 at 1 year, AND 3. Scale Inhibition of radiographic progression - Genant modified Sharp method 1. 20% improvement in American College of Rheumatology score at 6 months, AND 2. Scale Health Assessment Questionnaire Disability Index greater than 0.3 at day 169 1. Clinical response at week 6 (defined as decrease of over 100 in Crohn's Disease Activity Index), AND 2. 1. Clinical response at week 26 (defined as decrease of over 100 in Crohn's Scale Disease Activity Index) 1. Ocular itching score, AND 2. Conjunctival redness (9 step scales) Scale 1. Pre-bronchodilator forced expiratory volume in one second, AND 2. St George's Scale Respiratory Questionnaire score 1. 20% improvement in American College of Rheumatology score at week 14, AND 2. Scale Change from baseline in total radiographic scores of the hands and feet at 24 weeks 1. 20% improvement in American College of Rheumatology score at week 24, AND 2. Scale Change in baseline in Van der Heijde modified sharp score at week 52 Attention Deficit Hyperactivity Disorder Rating Scale Scale Aronchick Scale describing quality of bowel prep Scale

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Conjunctival allergen challenge induced allergic conjunctivitis symptoms at 15min and 16hrs (Ocular itching evaluated by the subject at 3, 5, and 7 minutes post challenge (0-4 unit scale) & Conjunctival redness evaluated by the investigator at 7, 15, and 20 minutes Scale post challenge (0-4 unit scale, allowing half unit increments) Change from baseline in Brief Psychiatric Rating Scale Scale Change from baseline on Toronto Western Spasmodic Torticollis Rating Scale (cervical Scale dystonia) score at week 4 evaluation Change from baselines in Toronto Western Spasmodic Torticollis Rating Scale total score Scale at visit 3 (week 4) Change in disease activity measured on daily health assessment forms Scale Change in Hamilton Rating Scale of Depression (17) score Scale Change in International Prostate Symptom Score Scale Change in International Restless Legs Scale from baseline to week 12, AND 2. Proportion of responders who rated their symptoms as "good" and "very good" on the Clinical Global Scale Impression (Investigator) Change in mean symptom complex score (hereditary angioedema) Scale Change in Positive and Negative Syndrome Scale Scale Change in total maximum Chorea Score (average of week 9 to week 12 scores compared Scale to baseline) Change in total Unified Parkinson's Disease Rating Scale from baseline to 6 months visit Scale Change in Young-Mania Rating Scale Scale Change in Unified Parkinson's Disease Rating Scale - Part II Scale Confirmed relapses (based on a clinical scale) Scale Glabellar severity score at maximum frown on day 30 (investigator and patient assessed) Scale Jankovic rating scale to assess blepharospasm six weeks after administration Scale Mean change from baseline in Montgomery–Åsberg Depression Rating Scale at 8 weeks Scale Median time to primary symptom improvement using visual analogue scale Scale Pain improvement from baseline using visual analog scale Scale Pain intensity difference Scale 75% reduction in Psoriasis Area and Severity Index at 12 weeks Scale Proportion of patients with Assessment of SpondyloArthritis International Society response Scale at week 14 Proportion of subjects who maintained vision (loss of fewer than 15 letters in Early Scale Treatment of Diabetic Retinopathy Study scale) from baseline Swanson, Kotkin, Agler, M-Flynn, and Pelham - Deportment Scale Scale Systemic Lupus Erythematosus Responder Index at 52 weeks Scale Time to 50% decrease in composite visual analogue score (abdominal pain, skin pain, skin Scale swelling) Total nasal symptom score (patient-reported: congestion, itching, sneezing) Scale 1. Change in average daily area under the curve in serum sodium from baseline up to day Surrogate 30, OR 2. Average daily area under the curve in serum sodium up to day 4 1. Hemoglobin concentration stabilization, AND 2. Number of packed red blood cell Surrogate transfusions 1. Objective response rate, AND 2. Progression Free Survival Surrogate 1. Platelet count, AND 2. Hemoglobin concentration, AND 3. Spleen and liver volumes Surrogate 28-day cure rate (proportion of patients with clearance of asexual parasitemia within 7 days Surrogate of starting treatment without recurrence in 28 days) Anterior chamber cell grade of 0 on day 8 Surrogate Blood Phenylalanine level Surrogate Change from baseline in diurnal intraocular pressure at 6 months Surrogate Change in hemoglobin concentration from baseline Surrogate Change in liver iron content Surrogate Change in pre-bronchodilator forced expiratory volume in one second Surrogate Change in serum sodium baseline over treatment duration Surrogate Change in sitting diastolic blood pressure Surrogate Change in spleen volume Surrogate

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Change in systolic blood pressure Surrogate Complete hematologic response and no evidence of leukemia Surrogate Complete or partial response (measured by number of blast cells) Surrogate Confirmed virologic response at week 24 (drop of at least 1 log 10 in viral load versus Surrogate baseline) Decrease of 2 points or more in Knodell necroinflammatory score (liver biopsy scoring Surrogate system) Durable platelet response (six weekly platelet counts >50x109/L) in last 8 weeks of Surrogate treatment Duration of severe neutropenia (absolute neutrophil count < 500) during cycle 1 Surrogate Eradication of Helicobacter Pylori at 8 weeks (confirmed by successive negative urea Surrogate breath tests) Erythema induced by simulated solar radiation Surrogate Erythroid response Surrogate Maximum tolerated dose Surrogate Exercise tolerance test duration Surrogate Graded response score related to parenteral nutrition volume reduction and duration at Surrogate weeks 16, 20, 24 Hemoglobin A1c Surrogate Hepatitis B virus deoxyribonucleic acid viral load Surrogate Hematologic response Surrogate Hemoglobin response rate (increase in serum hemoglobin concentration from baseline of > Surrogate 1 g/dL) Human immunodeficiency virus ribonucleic acid < 400 copies per mL Surrogate Improvement of treated veins on digital images Surrogate Incidence of new vertebral fracture Surrogate Investigator-assessed response rate Surrogate Latency to persistent sleep (measured by polysomnography) Surrogate Low density lipoprotein Surrogate Major cytogenetic response Surrogate Major cytogenetic response and major hematologic response Surrogate Mean change from baseline in diurnal intraocular pressure at weeks 2, 6 and 12 Surrogate Mean change in serum hemoglobin concentration Surrogate Mean change in percent predicted forced expiratory volume in one second Surrogate Nonsurgical resolution of symptomatic vitreomacular adhesion documented by optical Surrogate coherence tomography Normalization of mean urinary free cortisol without dose titration Surrogate Number of patients Muckle-Wells syndrome experiencing a disease flare as determined by Surrogate serum C-reactive protein and amyloid levels Objective Response Rate (Complete Response + Partial Response) Surrogate Percent change in sub-maximal exercise duration by cycle ergometer Surrogate Percent change in visceral adipose tissue Surrogate Percent cures (cell score + flare score) Surrogate Percent of patients with > 35% spleen volume reduction Surrogate Post-operative blood pressure effect Surrogate Pre-operative blood pressure effect Surrogate Proportion of patients with platelet count > 50,000 Surrogate Proportion of patients with uric acid < 6mg/dL ≥ 80% of the time Surrogate Proportion of subjects with trough asparaginase activity > 0.1 IU/mL Surrogate Recovery of upper and lower gastrointestinal motility Surrogate Reduction in growth hormone and insulin-like growth factor 1 Surrogate Response rate measured by Severity Weighted Assessment Tool (total body surface area Surrogate with disease) Sustained virologic response (i.e., undetectable hepatitis C virus ribonucleic acid 24 weeks Surrogate after therapy) Testosterone level < 0.5 Surrogate Therapeutic response (1. Loss of detectable Hepatitis B virus "E" antigen, AND 2. Alanine Surrogate

Downloaded From: https://jamanetwork.com/ on 09/25/2021 transaminase normalization, AND 3. serum hepatitis B virus deoxyribonucleic acid level) Time to sputum culture conversion during treatment Surrogate Time to tumor progression (radiographic) Surrogate Total cluster of differentiation 34+ cells collected by apheresis Surrogate Transfusion independence Surrogate Treatment outcome score at 4 hours Surrogate Tumor response rate (radiologic) Surrogate Urea, plasma and glutamine levels compared to baseline Surrogate Uric acid < 6mg/dL Surrogate Virologic success (< 50 copies human immunodeficiency virus ribonucleic acid) Surrogate

Intention-to-treat (ITT) population: Number of subjects receiving at least one dose of

treatment (study medication, comparator or placebo). In studies using a cross-over design, the

ITT population of subjects taking the study medication could not be recorded because subjects

often were exposed to both the study medication and comparator in the same trial.

Trial duration: Length of time in weeks between the time when the first dose of the drug was

administered and the time that the primary endpoint was measured. Two examples are used to

illustrate how trial length is calculated:

• Trial lasting one year in which the primary outcome is measured at 24 weeks. Trial

length = 24 weeks

• Trial evaluating an antibiotic in which subjects receive the study drug / placebo for 1

week and are then evaluated 2 weeks after the end of therapy to determine whether

they have been cured. The cure rate at end of therapy is the primary endpoint. Trial

length = 3 weeks

The median duration of treatment was used as a proxy for trial length in event- driven trials,

which measure the time to outcomes such as death (e.g., overall survival) or hospitalization.

When differences in trial length existed between treatment arms, a weighted average calculation

was used to determine a single value for trial length.

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Completion rate: Calculated by dividing the number of subjects completing all treatments in

trial by the ITT population. Generally, the number of subjects completing treatment was shown

in a table of subject disposition. For drugs treating cancer and infectious disease, patients that

discontinued the study drug because they reached an outcome, such as disease progression,

lack of efficacy or death, were considered to have completed the study and the completion rate

calculation was performed accordingly.

Information typically found in the “Review of Safety” (section 7) component of

FDA Medical Review

Safety population: The number of subjects included in the safety database is listed in the FDA

medical review. Typically, this is the number of subjects exposed to the investigational drug

during its clinical development. However, other definitions of safety population, such as subjects

exposed in phase III trials or subjects exposed in controlled trials, were used when explicitly

specified by the reviewer.

Downloaded From: https://jamanetwork.com/ on 09/25/2021