Acromegaly:  
Developing Drugs for 
Treatment 
Guidance for Industry 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Naomi Lowy at 301-796-0692.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
January 2023 
Clinical 
51677537dft.docx 
10/21/22   
Acromegaly:  
Developing Drugs for 
Treatment 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2023 
Clinical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................1 
III.  DEVELOPMENT PROGRAM ............................................................................2 
A.  General Considerations .................................................................................................... 2 
B.  Phase 3 Trial Design Considerations ............................................................................... 4 
C.  Phase 3 Eligibility Considerations ................................................................................... 6 
D.  Phase 3 Efficacy Endpoint Considerations ..................................................................... 7 
E.  Phase 3 Statistical Considerations ................................................................................... 8 
F.  Safety Considerations ...................................................................................................... 10 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Acromegaly:  Developing Drugs for Treatment  
2  Guidance for Industry1 
3   
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page. 
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  The purpose of this guidance is to provide recommendations to sponsors regarding clinical 
17  development of drugs for the treatment of patients with acromegaly. This draft guidance is 
18  intended to serve as a focus for continued discussions among the Division of General 
19  Endocrinology, pharmaceutical sponsors, the academic community, and the public.2   
20   
21  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
22  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
23  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
24  the word should in Agency guidances means that something is suggested or recommended, but 
25  not required.  
26   
27   
28  II.  BACKGROUND 
29   
30  Acromegaly is a chronic, rare disease in adults (50 to 70 people per million worldwide) caused 
31  by excess growth hormone (GH).3 The most common etiology is a GH-secreting pituitary 
32  adenoma that stimulates hepatic overproduction of insulin-like growth factor-1 (IGF-1). Signs 
33  and symptoms of acromegaly are caused by the adenoma compressing the surrounding structures 
34  (e.g., headaches, vision loss) and by the chronic overproduction of both GH and IGF-1 (bone and 
35  tissue overgrowth, diabetes, hypertension, fatigue, weakness, excessive perspiration, joint pain, 
36  edema, sleep apnea, and excessive snoring.)  
37   
38  Gigantism occurs with excessive growth hormone secretion in children. Because the 
39  manifestations of the disease are different, gigantism is not addressed in this guidance. Under 
 
1 This guidance has been prepared by the Division of General Endocrinology in the Center for Drug Evaluation and 
Research at the Food and Drug Administration (the division). 
 
2 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that 
arise during the development of drugs for the treatment of acromegaly. 
 
3 Melmed S, 2006, Acromegaly, N Engl J Med, 355(24):25582573. 
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40  certain circumstances, development of drugs for acromegaly may trigger the Pediatric Research 
41  Equity Act, and, if so, pediatric requirements may apply.4  
42   
43  First-line therapy for acromegaly is tumor resection, typically by transsphenoidal surgery. 
44  Second-line therapy includes stereotactic radiotherapy and medications that reduce IGF-1 
45  secretion. Guidelines from professional societies5,6 include recommendations for medical therapy 
46  for the following patients with acromegaly: those with persistent or recurrent disease despite 
47  surgery, those who are waiting for administered radiotherapy to effectively lower IGF-1 levels 
48  (which can take years), and those who are not candidates for surgery or radiotherapy because of 
49  poor health.  
50   
51  The goal of medical therapy is to normalize IGF-1 levels for age and sex and to decrease random 
52  GH levels below 1 mcg/L. Spontaneous remission of disease occurs occasionally; therefore, in 
53  patients who are biochemically controlled, periodic withdrawal of pharmacological treatment is 
54  recommended to assess whether the disease remains active in the absence of treatment.5,7 
55   
56  Drugs from several pharmacological classes are approved to treat acromegaly, including 
57  somatostatin analogs (octreotide, lanreotide, and pasireotide), a GH-receptor antagonist 
58  (pegvisomant), and a dopamine-receptor agonist (bromocriptine).   
59   
60  Historically, approved indications reflect two distinct clinical scenarios: 1) patients with 
61  uncontrolled disease who are treatment-naive or nonresponders to previous medical treatments 
62  (referred to as treatment of acromegaly in this guidance) and 2) patients whose disease is 
63  controlled on medical therapy and are switching to a different drug (referred to as maintenance 
64  of treatment in this guidance). To support approval of each indication, the appropriate 
65  populations should be included in distinct adequate and well-controlled investigations. 
66   
67   
68  III.  DEVELOPMENT PROGRAM 
69   
70  A.  General Considerations 
71   
72    The following are the overall objectives of the clinical development program for drugs 
73  intended for the treatment of acromegaly and for maintenance of treatment indications:  
74   
 
4 See section 505B(a)(1)(A) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355c(a)(1)(A)). 
 
5 Katznelson L, ER Laws Jr, S Melmed, ME Molitch, MH Murad, A Utz, and JAH Wass, 2014, Acromegaly: An 
Endocrine Society Clinical Practice Guideline, JCEM, 99(11):39333951. 
 
6 Giustina A, P Chanson, D Kleinberg, MD Bronstein, DR Clemmons, A Klibanski, AJ van der Lely, CJ 
Strasburger, SW Lamberts, KKY Ho, FF Casanueva, and S Melmed, 2014, Expert Consensus Document: A 
Consensus on the Medical Treatment of Acromegaly, Nat Rev Endocrinol, 10(4):243248. 
 
7 The Sandostatin LAR Depot labeling recommends yearly withdrawal to assess the disease activity in patients who 
received pituitary radiation. 
2  Contains Nonbinding Recommendations 
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75    Determine the pharmacokinetics (PK) and pharmacodynamics (PD) of the product in 

76  subjects with acromegaly 
77   
78    Evaluate the relationship between doses and/or exposure-response based on IGF-1 

79  levels in early phase studies to support dose selection for phase 3 pivotal studies 
80   
81    Establish the efficacy and safety of the drug in subjects with acromegaly 

82   
83    Selection of the dose or doses and dosing regimen for evaluation in the phase 3 study 
84  should be based on the results of the dose-response (IGF-1), pharmacokinetics and 
85  pharmacodynamics, and available efficacy and safety information obtained from a phase 
86  2 study. Refer to the draft guidance for industry Exposure-Response Relationships  
87  Study Design, Data Analysis, and Regulatory Applications (April 2003)8 and the ICH 
88  guidance for industry E4 Dose-Response Information to Support Drug Registration 
89  (November 1994).9 
90   
91    The selection of doses (starting and incremental doses or fixed doses) for phase 3 

92  studies should be based on either normalization of IGF-1 levels demonstrated in a 
93  phase 2 study or decreases in IGF-1 levels that are expected to produce normalization 
94  of IGF-1 levels with longer treatment in phase 3 studies. The study duration should 
95  account for the drugs half-life, time to achieve steady state, and PD half-life so that 
96  the effects of the drug on IGF-1 changes can be accurately assessed. 
97   
98    Other clinical pharmacological studies, including assessment of drug interactions10 and 
99  the impact of intrinsic and extrinsic factors on the pharmacokinetics and 
100  pharmacodynamics of the investigational product, should be conducted early in drug 
101  development to aid in the study design of later phase trials. 
102   
103    In acromegaly drug development programs, substantial evidence of effectiveness has 
104  been established with either two adequate and well-controlled trials or one adequate and 
105  well-controlled trial with confirmatory evidence. Refer to the draft guidance for industry 
106  Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological 
 
8 When final, this guidance will represent the FDAs current thinking on this topic. For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
 
9 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
10 See the guidances for industry In Vitro Drug Interaction StudiesCytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions (January 2020) and Clinical Drug Interaction StudiesCytochrome P450 Enzyme- and 
Transporter-Mediated Drug Interactions (January 2020) and the draft guidances for industry Evaluation of Gastric 
pH-Dependent Drug Interactions With Acid-Reducing Agents: Study Design, Data Analysis, and Clinical 
Implications (November 2020), Clinical Drug Interaction Studies With Combined Oral Contraceptives (November 
2020) and Drug-Drug Interaction Assessment for Therapeutic Proteins (August 2020). When final, these guidances 
will represent the FDAs current thinking on these topics.  
3  Contains Nonbinding Recommendations 
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107  Products (December 2019)11 for more information about establishing substantial 
108  evidence of effectiveness. 
109   
110    The phase 3 trial should be randomized and double-blinded and use placebo or an 

111  active control. Even though IGF-1 is an objective measure, an open-label design can 
112  affect the conduct of the study (e.g., enrollment and/or retention of subjects) and can 
113  limit interpretation of safety data. An extension phase should follow to obtain long-
114  term safety data.   
115   
116    Sponsors should consider the need for washout periods to minimize the residual effects of 
117  previous drugs on IGF-1 levels and to confirm persistent disease activity. Duration of 
118  washout periods should be drug-specific and based on the relevant drugs half-lives. 
119  Sponsors may propose a shorter washout period with appropriate justification. Factors to 
120  consider when deciding on the need for and duration of the washout period include the 
121  objectives of the trial, biological half-lives of prior therapies, and the primary efficacy 
122  time point. In addition, sponsors should consider how safety will be assessed if a 
123  complete washout is not proposed. 
124   
125    Sponsors proposing a shorter washout period should acknowledge within the protocol 

126  and informed consent the potential increased risk of adverse events because of 
127  residual drug activity in the early portion of the trial, and sponsors should include 
128  appropriate close monitoring and risk mitigation plans. 
129   
130    Given that acromegaly is a chronic disease, the safety database should include a sufficient 
131  number of subjects with acromegaly treated with the proposed product for at least 12 
132  months, including 6 months of controlled data. 
133   
134  B.  Phase 3 Trial Design Considerations 
135   
136    Placebo-controlled trials have been conducted to support approval of drugs to treat 
137  acromegaly. From an ethical perspective, this design is acceptable because treatment 
138  guidelines include the recommendation of periodic withdrawal of previous therapies, 
139  including subjects who require the lowest doses.12 In addition, monitoring and timely 
140  control of acromegaly-related comorbidities during the trial (e.g., with antidiabetic, 
141  antihypertensive medications) and other protocol safeguards (e.g., inclusion/exclusion 
142  criteria, rescue criteria) can ensure the safety of subjects while receiving placebo.  
143   
144    If an active-controlled trial uses a non-US-approved comparator, data should be provided 
145  to justify the scientific relevance of the comparative data. In such cases, sponsors should 
146  consult the review division regarding their approach.  
147   
148    If the test drug and comparator have different routes of administration or different 
149  regimens, the sponsor should consider a double-dummy trial design. FDA recognizes 
 
11 When final, this guidance will represent the FDAs current thinking on this topic. 
 
12 See footnote 5. 
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150  blinding may be a challenge in these situations and recommends sponsors consider using 
151  placebo if a double-dummy trial design is not feasible.  
152   
153    For clinical trials, disease control has been defined by biochemical control of IGF-1 
154  levels. Most symptoms of acromegaly are nonspecific, so a normal IGF-1 level in the 
155  presence of persistent symptoms has been considered controlled disease.  
156   
157    The randomized phase of the study should be at least 6 months in duration to allow 
158  sufficient time to titrate to an effective dose while minimizing dose-related adverse 
159  reactions and to demonstrate the maintenance of IGF-1 levels on the effective dose.   
160   
161    All phase 3 studies should generally include a titration period and a fixed-dose period that 
162  takes into account the drugs half-life and time to reach steady state.  
163   
164    The dose or doses of drug should not be increased during the fixed-dose period to 

165  better evaluate the durability of the effect of the drug.  
166   
167    All dose titrations during the trial should be based on IGF-1 levels with the goal to 

168  maintain IGF-1 within the normal reference range. 
169   
170    Intervals between up-titrations should be defined by PK parameters, including half-

171  life and time to reach steady state. 
172   
173    The dose should be down-titrated any time during the trial based on safety and 

174  tolerability of the drug.  
175   
176    Symptoms should not be used to guide dose up-titration during the study or studies, 

177  given that symptoms are nonspecific. 
178   
179    For periodic measurements intended to assess the need for dose-titration, a single IGF-1 
180  measurement is acceptable. 
181   
182    Rescue criteria should be clearly defined in the protocol, and for rescue a subject should 
183  meet both clinical and biochemical criteria. Biochemical criteria should define an IGF-1 
184  rescue threshold (e.g., IGF-1 > 1.3x upper limit of normal (ULN)). Clinical criteria can 
185  be based on symptoms or signs of worsening disease activity (e.g., worsening 
186  diaphoresis, fatigue, soft tissue swelling, hyperglycemia, hypertension). 
187   
188    Subjects whose disease activity cannot be controlled during the study while using the 
189  maximum dose of the study drug(s) should be rescued with approved, effective standard 
190  of care therapies. Subjects should not be terminated from trial data collection. They 
191  should continue to be followed until the final visit. 
192   
193   
194   
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195  C.  Phase 3 Eligibility Considerations 
196   
197    Clinical trials should target patients who would be recommended to receive medical 
198  therapy. These typically would include adults with confirmed active acromegaly who had 
199  an inadequate response to surgery and/or for whom surgery is not an option. 
200   
201    Diagnosis of active acromegaly should be confirmed by historically documented 
202  evidence of a GH-secreting pituitary tumor based on magnetic resonance imaging and/or 
203  pathology report and documented evidence of IGF-1 serum levels above ULN and lack of 
204  suppression of GH to < 1 mcg/L following documented hyperglycemia during an oral 
205  glucose load. 
206   
207    For a treatment of acromegaly indication, subjects should have uncontrolled disease at 
208  baseline, defined as elevated IGF-1 levels above the ULN in those who are treatment-
209  naive or those who were treated with other medical therapies for at least 6 months in the 
210  past and did not respond to the maximum dose or did not tolerate the previously used 
211  drug. 
212   
213    The elevated IGF-1 level should be based on two values obtained during screening 1 

214  to 2 weeks apart. One of the samples should be collected as close to randomization 
215  visit as possible (e.g., 1 to 2 weeks). 
216   
217    For a maintenance of treatment indication, subjects should have controlled disease while 
218  being treated with stable doses of other acromegaly drug(s) for an appropriate period of 
219  time based on the drugs half-life and steady state. Eligible subjects should have 
220  documented evidence of active acromegaly because not all patients who have normal 
221  IGF-1 while taking medical therapy necessarily have active disease. Continued disease 
222  activity can be confirmed by documentation of elevated IGF-1 levels within 1 year before 
223  enrollment or by withdrawal of drug therapy before randomization. 
224   
225    For a maintenance indication, disease control is defined as an average IGF-1 within 

226  the normal range calculated from two assessments 1 to 2 weeks apart during the 
227  screening period. Subjects should be on treatment with stable doses of previous drugs 
228  until screening. Prior disease activity should be documented in each subjects case 
229  report form or patient chart and be available for FDA review.   
230   
231    Subjects with concomitant conditions that are commonly associated with acromegaly 
232  (e.g., cardiovascular disease and diabetes) and older adults should be considered for the 
233  phase 3 program to help ensure that the study population better reflects the patient 
234  population likely to use the drug in clinical practice. Refer to the guidance for industry 
235  Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, Enrollment 
236  Practices, and Trial Designs (November 2020). 
237   
238    Subjects should be excluded if they: 
239   
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240    Had pituitary surgery within 6 months of enrollment or received radiation treatment 

241  within 5 years of enrollment. The effect of these treatment modalities may be delayed 
242  and confound efficacy results. 
243   
244    Have pituitary tumors near the optic chiasm. This is to avoid the risk of tumor 

245  expansion and compression of optic nerves during treatment.  
246   
247    Children under 17 years of age should not be included in the clinical development 
248  program for acromegaly because GH over-secretion has a different clinical presentation 
249  in this population (i.e., excessive growth or gigantism).  
250   
251    Because medical treatment of acromegaly during pregnancy is generally not 
252  recommended, pregnant women have not been included in clinical development 
253  programs.13 Enrollment of lactating women can be considered if the available safety data 
254  support their inclusion. 
255   
256  D.  Phase 3 Efficacy Endpoint Considerations 
257   
258    An average of two IGF-1 levels, generally within 1 to 2 weeks, should be obtained to 
259  confirm eligibility before randomization may be used as the baseline value.  
260   
261    The primary efficacy endpoint to support an acromegaly indication should be 
262  normalization of IGF-1 levels after at least 6 months of randomized therapy. 
263  Normalization of IGF-1 levels translates into improved signs and symptoms of the 
264  disease and ultimately decreases morbidity and mortality associated with acromegaly.   
265   
266    Although a decrease in GH levels to < 1 mcg/L also correlates with control of 
267  acromegaly, natural secretion of GH is pulsatile, leading to wide variations in plasma GH 
268  levels during the day. As such, a single GH value is not reliable in defining disease 
269  control, and collecting multiple samples during the day is time-consuming and 
270  inconvenient for subjects. GH levels can be evaluated as a secondary endpoint in support 
271  of the primary endpoint. These should be collected as multiple samples over 24 hours and 
272  averaged. 
273   
274    Both GH and IGF-1 should be measured by the programs central laboratory. 
275   
276    FDA recommends a responder analysis for the primary efficacy endpoint.  
277   
278    For a treatment indication, a responder is a subject with elevated IGF-1 levels at 

279  baseline who achieved normal IGF-1 levels at the end of the study and did not require 
280  a dose increase during the fixed-dose period.  
281   
 
13 See footnote 5. 
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282    For a maintenance indication, a responder is a subject with normal IGF-1 levels at 

283  screening and who has normal IGF-1 levels at the end of the study and did not require 
284  a dose increase during the fixed-dose period.  
285   
286    Subjects who required an increase in dose during the fixed-dose period or who did not 
287  have IGF-1 evaluation at the end of the treatment for any reason (missed samples, 
288  withdrawn earlier, etc.) should generally be considered as nonresponders in the primary 
289  analysis.  
290   
291    All IGF-1 and GH levels should be obtained at C , before the administration of the 
trough
292  next dose.  
293   
294    For the primary efficacy assessment, IGF-1 should be based on an average IGF-1 level of 
295  the last two available measurements (within 1 to 2 weeks of each other) at the end of the 
296  fixed-dose treatment period. Missing data raises issues of data quality and may interfere 
297  with analysis and interpretation of study results. When one of the two last IGF-1 
298  measurements is missing but the subject has not been discontinued from the study, a 
299  single value can be used for the study final assessment. However, FDA expects this to 
300  occur as an exception and strongly encourages sponsors to collect two values for the 
301  study final assessment. A significant amount of missing data can raise questions about 
302  data quality.  
303   
304    Many acromegaly symptoms are nonspecific (e.g., headache, fatigue, sweating) and may 
305  be related to concomitant medical conditions (e.g., hypertension, diabetes) or 
306  medications. These factors may make it challenging to show that the drug improves 
307  symptoms. If a sponsor wishes to show improvement of symptoms, we recommend using 
308  fit-for-purpose, patient-reported outcomes that assess the signs and symptoms of 
309  acromegaly as key secondary endpoints.14 Nonvalidated patient-reported outcomes 
310  should not be included as primary or key secondary efficacy endpoints and are 
311  appropriate as exploratory endpoints only.   
312   
313  E.  Phase 3 Statistical Considerations 
314   
315    Study protocols and statistical analysis plans should clearly prespecify the estimands of 
316  primary interest. The description of the estimands should reflect the clinical questions of 
317  interest with respect to intercurrent events.15 The statistical analyses should be aligned 
318  with the estimands of primary interest and clearly specify how the sponsor will account 
 
14 See the draft guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug Development: 
Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments (June 2022). When final, this 
guidance will represent the FDAs current thinking on this topic. 
 
15 Intercurrent events are events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest, for example, discontinuation of 
assigned treatment, use of prohibited medications, use of alternative or additional medications, and corrective 
surgery. See ICH E9(R1). 
 
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319  for intercurrent events and missing data.16 Sponsors should consult with FDA regarding 
320  these issues during the trial design stage. Sponsors should provide adequate justification 
321  that the proposed estimands address meaningful clinical questions of interest and can be 
322  estimated with plausible assumptions. Refer to the ICH guidance for industry E9(R1) 
323  Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis 
324  in Clinical Trials (May 2021) for more discussion on estimands and intercurrent events. 
325   
326    If a noninferiority trial design is considered, the choice of the active control and 
327  noninferiority margin should be discussed with the review division. Adequate 
328  justification of the noninferiority margin should be provided in the protocol and agreed 
329  upon by FDA. 
330   
331    Subjects should be stratified by history of radiation therapy and severity of the disease at 
332  baseline (based on IGF-1 levels at baseline or previous IGF-1 levels). 
333   
334    Subjects who receive rescue therapy for any reason should not be discontinued from the 
335  trial but rather should continue trial participation and follow all planned visits and 
336  assessments until the end of the trial. 
337   
338    Missing data are measurements that were planned to be collected and used for estimating 
339  a target estimand but were not available at the end of study. The existence of missing data 
340  increases uncertainty in estimation. The amount of missing data should be minimized. 
341  Refer to the National Research Council report on missing data for operational measures 
342  to prevent missing data.17 
343   
344    Despite the best precautions, some data will inevitably be missing. How the statistical 
345  analyses will account for missing data should be prespecified in the statistical analysis 
346  plan. Missing data should be imputed in a fashion consistent with what the values would 
347  likely have been had they been collected, with the corresponding uncertainty. We 
348  generally recommend that missing data be multiply imputed using appropriate methods 
349  based on plausible assumptions. Multiple imputations may be aggregated using Rubins 
350  method. For noninferiority comparisons, an imputation under the noninferiority null 
351  approach should be considered. 
352   
353    The imputation of missing data typically relies on assumptions that may not be verifiable. 
354  To assess the sensitivity of results to such uncertainty, sensitivity analyses such as tipping 
355  point analyses should be conducted that vary assumptions about the missing data. The 
356  tipping point analyses should allow assumptions about the missing outcomes on the two 
357  treatment arms to vary independently and should also include scenarios where missing 
358  data on one treatment indicates worse outcomes than missing data on the other treatment. 
359  The goal is to evaluate the plausibility of the assumed expected values for missing 
 
16 Missing data consist of withdrawal of informed consent for collection of additional data, missed clinical visits, 
and loss to follow-up. 
 
17 National Research Council, 2010, The Prevention and Treatment of Missing Data in Clinical Trials, Washington, 
DC: The National Academies Press. 
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360  outcomes on each treatment arm under which the conclusions change (i.e., under which 
361  there is no longer evidence of a treatment effect). For continuous data, we recommend 
362  performing the tipping point analysis by adding a sequence of constant values ranging 
363  from negative to positive numbers to the imputed values from the analysis that most 
364  appropriately addresses missing data. 
365   
366    The number of subjects in confirmatory trials should provide adequate power (e.g., 80 
367  percent) to evaluate the primary endpoint.    
368   
369    The primary analysis model should estimate the difference and its associated confidence 
370  intervals in rate of responders between treatment groups and should incorporate as factors 
371  prognostic covariates as well as any variables used to stratify the randomization.  
372   
373    If statistical significance is achieved on the primary endpoint, the type I error rate should 
374  be controlled across all clinically relevant secondary efficacy endpoints intended for 
375  product labeling. 
376   
377    Graphical methods showing IGF-1 values over time should be presented, and additional 
378  graphical presentations of the data to illustrate the effect of the drug are encouraged. For 
379  example, see the guidance for industry Clinical Studies Section of Labeling for Human 
380  Prescription Drug and Biological Products  Content and Format (January 2006). 
381   
382  F.  Safety Considerations 
383   
384  Clinical safety assessments should include pituitary tumor size monitoring; injection site 
385  reactions, if applicable; evaluation of hypersensitivity reactions as an adverse event of special 
386  interest if the investigational product is associated with development of antidrug antibodies; and 
387  other adverse events of interest based on the drugs pharmacology, toxicology, or known class 
388  effects (e.g., gastrointestinal adverse events, cholelithiasis, blood glucose abnormalities, cardiac 
389  function abnormalities). 
10