Endogenous Cushings 
Syndrome: 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DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Dockets Management Staff (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) 
 
September 2023 
Clinical/Medical
53358325dft 
08/28/23   
Endogenous Cushings 
Syndrome: 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) 
 
September 2023 
Clinical/Medical
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................1 
III.  DEVELOPMENT PROGRAM ............................................................................3 
A.  General Considerations .................................................................................................... 3 
B.  Phase 3 Development Program Considerations .............................................................. 4 
1. Drug Development Population ............................................................................................ 4 
2. Inclusion Criteria ................................................................................................................ 4 
3. Exclusion Criteria ............................................................................................................... 5 
4. Choice of Comparator ......................................................................................................... 6 
5. Efficacy Endpoints ............................................................................................................... 6 
6. Safety Considerations .......................................................................................................... 8 
7. Trial Procedures and Timing of Assessments ................................................................... 10 
8. Statistical Considerations .................................................................................................. 12 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Endogenous Cushings Syndrome:  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 trial 
17  designs for drugs and biologics2 intended for the treatment of adults with endogenous Cushings 
18  syndrome for whom surgery is not an option or has not been curative. This guidance does not 
19  address development of drugs and biologics for the treatment of exogenous Cushings syndrome. 
20  This guidance is intended to focus continued discussions among FDAs Division of General 
21  Endocrinology, pharmaceutical sponsors, the academic community, and the public.3 This is the 
22  first guidance drafted by FDA on this topic.  
23   
24  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
25  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
26  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
27  the word should in Agency guidances means that something is suggested or recommended, but 
28  not required.  
29   
30   
31  II.  BACKGROUND 
32   
33  Endogenous Cushings syndrome is a rare condition in which there is production of 
34  inappropriately high levels of circulating glucocorticoids from the adrenal gland for a prolonged 
 
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.  
 
2 For the purposes of this guidance, all references to drugs include drugs approved under section 505 of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) and therapeutic biological products licensed under 
section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262) that are regulated as drugs. 
 
3 In addition to consulting guidances, sponsors are encouraged to contact the Division of General Endocrinology to 
discuss specific issues that arise during the development of drugs for the treatment of endogenous Cushings 
syndrome. 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
35  period. The estimated annual incidence in the United States is 49 cases per million per year.4  
36   
37  Endogenous Cushings syndrome includes adrenocorticotropic hormone (ACTH)-dependent and 
38  ACTH-independent subtypes. Most cases of Cushings syndrome (80%) are ACTH-dependent 
39  and are caused by oversecretion of ACTH. Etiologies of the ACTH-dependent subtype include a 
40  pituitary adenoma (Cushings disease); ectopic ACTH secretion from an ACTH-producing 
41  tumor; and, rarely, ectopic corticotropin-releasing hormone (CRH) secretion from a CRH-
42  producing tumor. The less common ACTH-independent subtype is caused by autonomous 
43  oversecretion of glucocorticoids by the adrenal gland. Etiologies include an adrenal adenoma, 
44  adrenal carcinoma, macronodular adrenal hyperplasia, and primary pigmented nodular adrenal 
45  disease. 
46   
47  Cushings syndrome is characterized by systemic symptoms of hypercortisolism such as easy 
48  bruising, facial plethora, proximal myopathy, striae, fatigue, depression, decreased concentration, 
49  dorsocervical fat pad hypertrophy, supraclavicular fullness, facial fullness, osteoporosis, 
50  peripheral edema, hypokalemia, thin skin, poor skin healing, and metabolic syndrome 
51  (hypertension, weight gain, type 2 diabetes mellitus).5 Cardiovascular complications are the main 
52  cause of death for patients with Cushings syndrome, and the risk of death is independently 
53  increased by coexisting diabetes mellitus and/or hypertension.6  
54   
55  Recommended first-line treatment of patients with Cushings syndrome is surgical resection of 
56  the primary lesion or lesions.7 Radiotherapy and/or medical therapy are second-line treatments 
57  for patients who have undergone noncurative surgery or who are not surgical candidates. The 
58  goal of medical therapy is to control hypercortisolemia either by normalizing cortisol levels (i.e., 
59  urinary free cortisol (UFC) upper limit of normal (ULN)) or by blocking the cortisol action at 
60  its receptors. Lifelong medical treatment to suppress cortisol levels and/or action may be 
61  required if the primary cause of Cushings syndrome cannot be treated successfully with surgery 
62  and/or radiation.  
63   
64  Drugs of different pharmacological classes are approved for the treatment of Cushings disease 
65  and/or Cushings syndrome or for the treatment of symptoms (e.g., hyperglycemia) associated 
66  with Cushings syndrome. These drugs include somatostatin analogs that inhibit pituitary ACTH 
67  secretion, steroidogenesis inhibitors that act at the level of the adrenal glands, and glucocorticoid 
68  receptor blockers. 
 
4 Broder MS, Neary MP, Chang E, Cherepanov D, and Ludlam WH, 2015, Incidence of Cushings Syndrome and 
Cushings Disease in Commercially-Insured Patients <65 Years Old in the United States, Pituitary, 18(3):283289. 
 
5 Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, and Montori VM, 2008, The 
Diagnosis of Cushings Syndrome: An Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab, 
93(5):15261540. 
 
6
 Clayton RN, Raskauskiene D, Reulen RC, and Jones PW, 2011, Mortality and Morbidity in Cushings Disease 
over 50 Years in Stoke-on-Trent, UK: Audit and Meta-Analysis of Literature, J Clin Endocrinol Metab, 96(3):632
642. 
 
7 Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, and Tabarin A, 2015, Treatment 
of Cushings Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 100(8):2807
2831. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
69   
70  III.  DEVELOPMENT PROGRAM 
71   
72  A.  General Considerations 
73   
74  The following are the overall objectives of a clinical development program for a drug intended 
75  for the treatment of Cushings syndrome: determine the pharmacokinetics and 
76  pharmacodynamics of the drug in subjects with Cushings syndrome, evaluate the dose (and/or 
77  exposure)-response relationship to support dose selection for phase 3 pivotal studies, and 
78  establish the efficacy and safety of the drug in subjects with Cushings syndrome. 
79   
80  Selection of the dosing regimen for evaluation in phase 3 should be based on the results of the 
81  dose (and/or exposure)-response (the measured response depends on the mechanism of action of 
82  the drug and may include reduction in UFC, ACTH, blood glucose, blood pressure), 
83  pharmacokinetics, pharmacodynamics, and available efficacy and safety information obtained, 
84  typically from a phase 2 trial (refer to the guidance for industry Exposure-Response 
85  Relationships  Study Design, Data Analysis, and Regulatory Applications (April 2003)8 and 
86  the ICH guidance for industry E4 Dose-Response Information to Support Drug Registration 
87  (November 1994)).  
88   
89  Other clinical pharmacology studies, including assessment of drug interactions9 and the impact 
90  of intrinsic and other extrinsic factors on the pharmacokinetics and pharmacodynamics of the 
91  investigational drug, should be conducted early in drug development to aid in the trial design of 
92  later phase trials. 
93   
94  In Cushings syndrome drug development programs, approaches to establish substantial evidence 
95  of effectiveness include two adequate and well-controlled trials or one adequate and well-
96  controlled trial plus confirmatory evidence.10 In certain cases, a well-designed and executed 
97  phase 2 trial can serve as one of the adequate and well-controlled trials. Refer to the draft 
98  guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
99  Biological Products (December 2019)11 for more information about establishing substantial 
100  evidence of effectiveness. 
 
8 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.  
 
9 See the guidances for industry In Vitro Drug Interaction StudiesCytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions (January 2020), Clinical Drug Interaction StudiesCytochrome P450 Enzyme- and 
Transporter-Mediated Drug Interactions (January 2020), Evaluation of Gastric pH-Dependent Drug Interactions 
With Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications (March 2023), Clinical Drug 
Interaction Studies With Combined Oral Contraceptives (June 2023), and Drug-Drug Interaction Assessment for 
Therapeutic Proteins (June 2023).  
 
10  See FD&C Act section 505(d) (21 U.S.C. 355(d)).  For a drug product to be approved by FDA, a sponsor must 
provide substantial evidence that the drug has the effect it purports to have under the conditions of use described in 
the proposed labeling and that the drugs benefits outweigh the risks.  Generally, the evidence is derived from 
adequate and well-controlled clinical studies.  
  
11 When final, this guidance will represent the FDAs current thinking on this topic. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
101   
102  Phase 3 trials should be randomized, double-blind, and placebo- or active-controlled. An 
103  extension phase of at least 6-month duration should follow to obtain durability of response and 
104  long-term safety data. 
105   
106  B.  Phase 3 Development Program Considerations 
107   
108  1.  Drug Development Population  
109   
110  The phase 3 development program should include subjects with confirmed Cushings syndrome 
111  who are candidates for medical therapy according to current medical practice (i.e., subjects with 
112  persistence or recurrence of hypercortisolism despite surgery and/or for whom surgery is not an 
113  option).  
114   
115  The proposed indication for the drug should reflect the disease subtypes and endpoints studied in 
116  the pivotal phase 3 trials. Because some subtypes of Cushings syndrome are rare (e.g., ectopic 
117  ACTH syndrome, adrenal carcinoma, pituitary carcinoma) and it may be challenging to enroll an 
118  adequate number of subjects with those subtypes in a clinical trial, FDA will review all available 
119  data obtained in even a limited number of subjects. FDA may also consider how data from a 
120  broader Cushings syndrome clinical trial population may apply to the treatment of rarer 
121  subtypes, potentially based on the drugs mechanism of action. For example, sponsors may 
122  provide a rationale that data from clinical trials of steroidogenesis inhibitors in subjects with 
123  Cushings disease can support approval of the drug for patients with Cushings syndrome of 
124  other rarer subtypes given that the drug inhibits cortisol synthesis, irrespective of the underlying 
125  pathophysiology. 
126   
127  Sponsors should also address how the efficacy or dosage of the drug may be affected by 
128  differences in the pathogenesis or manifestations of these subtypes. For example, a higher dosage 
129  of the drug may be needed to treat higher cortisol levels associated with more aggressive 
130  subtypes of Cushings syndrome (e.g., ectopic ACTH secretion). If there is adequate justification 
131  to support the applicability of these data to patients with rare subtypes, this approach may 
132  obviate the need for inclusion of many of those subjects in a clinical trial. To best support a 
133  broader proposed indication (e.g., in more Cushings syndrome subtypes), however, sponsors 
134  should make every attempt to include as many subjects with the rarer subtypes as possible. 
135   
136  2.  Inclusion Criteria  
137   
138  For trials of drugs that either decrease cortisol levels or block the action of cortisol, FDA 
139  recommends the following inclusion criteria, at a minimum: 
140   
141    Subjects who have persistent or recurrent hypercortisolism because of endogenous 
142  Cushings syndrome more than 6 weeks after surgery and/or who are not candidates for 
143  surgery or refuse to undergo surgery 
144   
145    Cushings syndrome confirmed by the presence of the following: 
146   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
147    UFC above ULN from a minimum of two adequate urinary collections (i.e., adequate 

148  urinary volume and creatinine clearance) collected at least 1 week apart. FDA 
149  recommends sponsors use threshold of 1.5x ULN for UFC to increase the specificity 
150  of the test and exclude subjects with pseudo-Cushings syndrome.   
151   
152    In addition to elevated mean UFC, presence of either abnormal dexamethasone 

153  suppression test or elevated late-night salivary cortisol. 
154   
155  Sponsors should consider the need for adequate washout periods primarily to address and 
156  minimize the residual effects of previous drugs on UFC levels. Duration of washout periods 
157  should be drug-specific and based on the relevant drugs half-lives.  
158   
159  For trials of drugs that block cortisol receptors and/or cortisol action but do not decrease cortisol 
160  levels, FDA recommends the following inclusion criteria, at a minimum: subjects with 
161  glucocorticoid-induced diabetes, glucocorticoid-induced impaired glucose tolerance, or 
162  glucocorticoid-induced hypertension at baseline. Because serum cortisol levels are not reliable 
163  for assessing the effect of drugs that block cortisol receptors and/or cortisol action at its 
164  receptors, the effect of the drug on downstream effects of cortisol, such as hyperglycemia and/or 
165  hypertension, should be assessed. The appropriateness and clinical meaningfulness of other 
166  endpoints should be discussed with FDA. 
167   
168  3.  Exclusion Criteria 
169   
170  For trials of drugs that either decrease cortisol levels or block the action of cortisol, FDA 
171  recommends the following exclusion criteria, at a minimum: 
172   
173    Subjects who have undergone surgery to treat Cushings syndrome within 6 weeks before 
174  screening.  
175   
176    Subjects who received pituitary radiation therapy within 3 years of screening.  
177   
178    Subjects without overt Cushings syndrome, including those with autonomous cortisol 
179  secretion,12 pseudo-Cushings, or cyclic Cushings syndrome. To exclude subjects with 
180  cyclic Cushings syndrome, sponsors should document UFC 1.5x ULN from at least 
181  two urinary collections obtained at least 1 week apart.  
182   
183  For trials of drugs that block cortisol receptors and/or cortisol action but do not decrease cortisol 
184  levels (therefore endpoints include glucose- and blood pressure-related parameters), sponsors 
185  should consider excluding subjects with a long-standing history (before Cushings diagnosis) of 
186  type 1 or type 2 diabetes or preexisting diabetes, preexisting impaired glucose tolerance, or 
187  preexisting hypertension, to optimally avoid confounding effects.   
188   
 
12 Aron D, Terzolo M, and Cawood TJ, 2012, Adrenal Incidentalomas, Best Pract Res Clin Endocrinol Metab, 
26(1):6982. 
 
5  Contains Nonbinding Recommendations 
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189  4.  Choice of Comparator  
190   
191  Placebo-controlled trials have been conducted to support approval of drugs for the indication of 
192  both Cushings syndrome and Cushings disease. Although some stakeholders have raised 
193  concerns about the ethics of a placebo control, this design is regarded as acceptable because 
194  monitoring and timely control of Cushings syndromerelated comorbidities during the trial 
195  (e.g., with antidiabetic drugs and antihypertensive drugs) and other protocol safeguards (e.g., 
196  inclusion and exclusion criteria, withdrawal criteria) can ensure the safety of subjects. Limitation 
197  of the trial duration in a placebo-controlled trial can minimize other disease-related impacts, 
198  including osteoporosis, infection, and muscle loss.  
199   
200  Active-controlled trials should use a U.S.-approved drug as a comparator, dosed according to the 
201  recommended dosage in FDA-approved labeling, and titrated, as tolerated, to the maximum 
202  recommended approved dosage in subjects who do not adequately respond to the lower dosages. 
203  If the test drug and comparator have different routes of administration or different regimens, 
204  sponsors should consider a double-dummy trial design in order to yield interpretable efficacy and 
205  safety data.  
206   
207  5.  Efficacy Endpoints 
208   
209  The choice of efficacy endpoints should reflect the drugs mechanism of action. UFC is a reliable 
210  marker to assess the efficacy of drugs that inhibit either pituitary ACTH secretion or adrenal 
211  steroidogenesis. In contrast, UFC is not a reliable biomarker for drugs that block cortisol 
212  receptors. Efficacy for this class of drugs should be established by assessing their impact on 
213  downstream effects of cortisol at the glucocorticoid receptor.  
214   
215  For drugs that decrease cortisol levels/inhibit cortisol synthesis: 
216   
217  FDA accepts as a primary efficacy endpoint the sustained normalization of mean UFC levels 
218  (i.e., UFC ULN) after a titration phase followed by a fixed-dose period of adequate duration. 
219  Treatment guidelines13 recommend normalization of UFC as the goal of therapy because 
220  normalization is associated with reduced morbidity and mortality. Furthermore, UFC is an 
221  objective endpoint and is supported by clear mechanistic rationale. All currently marketed drugs 
222  that decrease cortisol levels in patients with Cushings syndrome were approved based on the 
223  biochemical control of the disease, (i.e., normalization of UFC levels).  
224   
225  The primary efficacy analysis should be a responder analysis, in which a responder is a subject 
226  with elevated UFC levels at baseline who achieved normal UFC levels at the end of the trial. 
227  Absolute change in UFC levels from baseline to end of treatment is not a meaningful endpoint 
228  because there is lack of consensus on what constitutes an important change from baseline in UFC 
229  levels. Rather, per treatment guidelines, normalization of UFC is indicative of disease control.  
230  Because UFC levels can fluctuate in patients with Cushings syndrome, mean UFC levels from a 
231  minimum of two adequate urinary collections at both baseline and endpoint should be used for 
232  the primary efficacy analysis. Subjects who required a dose increase during the fixed-dose 
 
13 See the Treatment of Cushings Syndrome Guideline Resources web page, available at 
https://www.endocrine.org/clinical-practice-guidelines/treatment-of-cushing-syndrome#1. 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
233  period, required rescue therapy, or did not have a final UFC evaluation for any reason (e.g., 
234  missed samples, premature withdrawal) should be considered nonresponders in the primary 
235  analysis.  
236   
237  For drugs that block glucocorticoid receptors and/or cortisol action but do not decrease cortisol 
238  levels:  
239   
240  The primary efficacy endpoint should reflect a downstream effect of cortisol action at the 
241  glucocorticoid receptor. FDA recommends using primary efficacy endpoints that reflect cortisol 
242  action, for example: glycemic control for subjects who have glucocorticoid-induced type 2 
243  diabetes or impaired glucose tolerance at baseline and/or change in blood pressure values for 
244  subjects who have glucocorticoid-induced hypertension at baseline. If sponsors plan to use other 
245  measures of cortisol action as primary endpoints, FDA recommends that sponsors provide 
246  justification to FDA for that plan and seek FDAs agreement before using such measures as 
247  primary endpoints.  
248   
249  For subjects with glucocorticoid-induced type 2 diabetes or impaired glucose tolerance at 
250  baseline: 
251   
252  Area under the curve for glucose (AUC ) with an oral glucose tolerance test (oGTT) has 
glucose
253  been accepted as a laboratory measure to demonstrate an effect of diminished cortisol action that 
254  is likely to be associated with clinical benefit because improvement in AUC  is a 
glucose
255  pharmacodynamic marker for cortisol action. AUC  is calculated using frequent 
glucose
256  measurements to minimize variability.  
257   
258  FDA has not accepted changes in a 2-hour oGTT or hemoglobin A1c (A1c) as markers to 
259  demonstrate the effect of diminished cortisol action on hyperglycemic control because results of 
260  a 2-hour oGTT can be highly variable and therefore unreliable to assess efficacy. Similarly, the 
261  clinical significance of an improvement in A1c in subjects with Cushings syndromeinduced 
262  impaired glucose tolerance, but without diabetes, who may have normal A1c at baseline is 
263  unknown.  
264   
265  FDA has accepted a responder analysis in which a response is defined as a reduction in 
266  AUC  by 25% from baseline to the end of the treatment period. Subjects who either require 
glucose
267  an increase in the dose of the investigational drug during the fixed-dose period or rescue therapy 
268  with antihyperglycemic drugs, or those with a missing final AUC  evaluation for any reason 
glucose
269  (e.g., missed samples, early withdrawal) should be considered as nonresponders. Analyses 
270  considering AUC  as a continuous variable should also be performed to facilitate 
glucose
271  interpretation of the results from the responder analysis. 
272   
273  The effect of the drug on AUC  should be supported by data from secondary endpoints, 
glucose
274  including changes in A1c and antidiabetic medications in subjects with diabetes (e.g., proportion 
275  of subjects who initiated new antidiabetic medications or received dose increases in antidiabetic 
276  medications, or proportion of subjects who discontinued antidiabetic treatment or had their dose 
277  reduced during the trial).  
278   
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279  For subjects with glucocorticoid-induced hypertension: 
280   
281  Change in mean systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) from 
282  baseline to the end of the treatment period based on ambulatory blood pressure monitoring is an 
283  objective laboratory measure to demonstrate an effect of diminished cortisol action in subjects 
284  with glucocorticoid-induced hypertension. To evaluate the pressor effects of drugs, FDA has 
285  accepted 1) a responder analysis in which a response is defined as 5 mmHg reduction in mean 
286  SBP and/or DBP without worsening of either and without any modification in antihypertensive 
287  medications attributable to worsening hypertension, or 2) a mean decrease in 24-hour average 
288  systolic blood pressure. Subjects who require an increase in the dose of the investigational drug 
289  during the fixed-dose period, require rescue therapy with antihypertensive drugs, or do not have 
290  final ambulatory blood pressure monitoring evaluation for any reason (e.g., missed samples, 
291  withdrawn earlier, etc.) should be considered as nonresponders.  
292   
293  The following secondary endpoints should be assessed to support the primary endpoint:  
294   
295    Mean difference in 24-hour average SBP (if not the primary endpoint), DBP, and heart 
296  rate  
297   
298    Mean difference in daytime and nighttime average SBP, DBP, and heart rate  
299   
300    Mean difference in SBP, DBP, and heart rate at the end of treatment period 
301   
302    Proportion of subjects who initiated new or discontinued previous antihypertensive 
303  medication during the trial  
304   
305    Proportion of subjects with dose increases or decreases in antihypertensive medication 
306  during the trial 
307   
308  6.  Safety Considerations  
309   
310  Because Cushings syndrome is a chronic disease, the safety database should include a sufficient 
311  number of subjects with Cushings syndrome treated with the proposed drug for at least 12 
312  months (typically approximately 150 subjects). If new safety issues arise in the nonclinical14 
313  program or during the phase 3 clinical program, FDA may recommend that sponsors conduct 
314  additional nonclinical studies or clinical trials and/or trials of longer duration to evaluate the new 
315  safety signals.  
316   
317  At a minimum, clinical safety assessments should include monitoring of the following adverse 
318  events of special interest:  
319   
320    Pituitary tumor enlargement in subjects with Cushings disease 
 
14 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible. We 
encourage sponsors to consult with us if it they wish to use a nonanimal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.   
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321   
322    Adrenal insufficiency 
323   
324    Serum cortisol levels may be needed to differentiate adrenal insufficiency from 

325  cortisol withdrawal syndrome in trials evaluating drugs that inhibit cortisol synthesis. 
326  Serum cortisol levels < 5.4 g/dl are diagnostic of adrenal insufficiency that is a life-
327  threatening condition and is associated with such serious symptoms as hypotension, 
328  electrolyte disturbances, dehydration, loss of consciousness, and ultimately death if 
329  left unrecognized and untreated. The treatment is immediate discontinuation of the 
330  drug and treatment with glucocorticoids. On the other hand, cortisol withdrawal 
331  syndrome is attributable to the fact that most patients with hypercortisolemia poorly 
332  tolerate low normal levels of cortisol or rapid decrease in cortisol levels (rather than 
333  attributable to low absolute cortisol levels). The signs and symptoms associated with 
334  rapid decrease in cortisol levels are similar to symptoms of true adrenal insufficiency 
335  (e.g., nausea, vomiting, fatigue); however, rapid cortisol decrease is non-life-
336  threatening because the absolute levels of cortisol remain within normal limits. This 
337  condition is usually self-limiting or requires dose decrease/interruption; treatment 
338  with glucocorticoids is rarely required. In general, to control hypercortisolemia 
339  associated with Cushings syndrome it is recommended to achieve cortisol levels 5.4-
340  10.8 g/dl.15 
341   
342    Serum cortisol levels are not reliable for the diagnosis of adrenal insufficiency or 

343  cortisol withdrawal syndrome in patients treated with cortisol receptor antagonists. 
344  Thus, in trials evaluating cortisol receptor antagonists, sponsors should incorporate 
345  appropriate monitoring based on signs and symptoms of adrenal insufficiency as part 
346  of their safety evaluation. Sponsors should prespecify in the protocol the signs and 
347  symptoms of adrenal insufficiency that may require a dose decrease and/or treatment 
348  discontinuation.  
349   
350    FDA does not recommend relying on levels of UFC to diagnose adrenal insufficiency 

351  or cortisol withdrawal syndrome because of high variability in levels.  
352   
353    The protocol should specify criteria for rescue therapy with glucocorticoids and 

354  treatment discontinuation or interruption followed by restarting with lower doses.  
355   
356    For drugs that block cortisol receptors and/or cortisol action at its receptors, symptoms 
357  associated with activation of mineralocorticoid receptors (e.g., hyperaldosteronism-like 
358  symptoms such as elevated blood pressure, low potassium levels) 
359   
 
15 Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, and Tabarin A, 2015, Treatment 
of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab, 100(8):2807
2831. 
 
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Draft  Not for Implementation 
360    For cortisol synthesis inhibitors, adverse events associated with potential accumulation of 
361  steroid hormone precursors (e.g., 11- deoxycorticosterone, 11-deoxycortisol),16 including 
362  hirsutism, acne, hypokalemia, hypertension, and edema  
363   
364  7.  Trial Procedures and Timing of Assessments 
365   
366    The main phase of phase 3 trials should include a drug titration period to allow titration to 
367  achieve normalization of UFC or maximum tolerable dosage followed by a fixed-dose 
368  period of sufficient duration during which the doses should not be increased to evaluate 
369  efficacy and durability. Sponsors should consider the half-life of the drug and discuss it 
370  with FDA when deciding the duration of the fixed-dose period.  
371   
372    Depending on the mechanism of action of the drug, the titration period should be long 

373  enough to achieve the maximum dosage of the drug needed to either normalize UFC 
374  levels or to demonstrate an improvement in glucocorticoid-induced hyperglycemia or 
375  hypertension. 
376   
377    Dose titration should be based on objective measures (e.g., UFC level for drugs that 

378  decrease cortisol secretion; or plasma glucose values, mean 24-hr SBP and/or DBP, 
379  etc., for drugs that block glucocorticoid receptors and/or cortisol action but do not 
380  decrease cortisol levels) and safety signals (e.g., onset of adrenal insufficiency).  
381   
382    Improvement in symptoms should not be used to guide dose up-titration. Symptoms 

383  can be nonspecific and may be subject to bias. In addition, resolution of symptoms 
384  may be delayed following normalization of cortisol levels.  
385   
386    For trials of drugs that block cortisol receptors and/or cortisol action but do not decrease 
387  cortisol levels, subjects should be assigned at time of randomization to either a 
388  glucocorticoid-induced hyperglycemia subgroup or a glucocorticoid-induced 
389  hypertension subgroup for the analysis of efficacy endpoints, depending on which 
390  abnormality they have at baseline. The protocol should also prespecify whether subjects 
391  with concomitant glucocorticoid-induced diabetes/impaired glucose tolerance and 
392  hypertension will be assigned to either one or both subgroups, and whether subjects who 
393  have improvement in one endpoint and worsening or no improvement in the other 
394  endpoint will be classified as responders or nonresponders. 
395   
396    For UFC measurement in trials of investigational drugs that decrease cortisol 
397  levels/inhibit cortisol synthesis, the following are recommended: 
398   
399    Baseline assessment: An average of at least two UFC levels obtained within 1 to 2 

400  weeks before randomization should be used for the baseline assessment.  
401   
402    Efficacy assessment: UFC level should be based on an average of at least two UFC 

403  levels obtained within 1 to 2 weeks at the end of the fixed-dose period. This might 
 
16 These precursors may reflect the shift of steroidogenesis toward the androgen pathway. Precursors other than 
adrenal hormonal precursors may accumulate. 
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404  lead to missing data, and a single last value can be used for the final trial assessment. 
405  However, FDA expects that this will occur only in a minority of subjects, if any. A 
406  significant amount of missing data can raise questions about data quality, which may 
407  lead to uncertainties about the trial results.  
408   
409    Dose titration should generally be based on mean UFC values calculated from at least 

410  two UFC samples.  
411   
412    Central laboratory assays should be used for all UFC measurements.  

413   
414    For the drugs that block cortisol receptors and/or cortisol action but do not decrease 
415  cortisol levels, the following are recommended for subjects with glucocorticoid-induced 
416  type 2 diabetes or impaired glucose tolerance at baseline: 
417   
418    AUC  should be calculated based on oGTT values. A 2-hr oGTT should be 
 glucose
419  obtained for all subjects at baseline (i.e., 1 to 2 weeks before randomization) and at 
420  regular intervals for subjects who have diabetes or impaired glucose tolerance at 
421  baseline. oGTT should be obtained within 1 week of the end of the fixed-dose period 
422  for the calculation of AUC  for the efficacy assessment. 
glucose
423   
424    A1c should be obtained for all subjects at baseline (i.e., 1 to 2 weeks before 

425  randomization) and then every 3 months.  
426   
427    Efficacy assessment (secondary endpoint):  

428   
429    Change in A1c in the subgroup of subjects with glucocorticoid-induced diabetes 
430  at baseline after at least 3 months of treatment should be included as a secondary 
431  endpoint to provide supportive evidence of efficacy of the drug.  
432   
433    A1c obtained within 1 week of the end of fixed-dose period should be used for the 
434  efficacy assessment.  
435   
436    Changes in dose(s) and/or number of antidiabetic medications.  
437   
438    For the drugs that block cortisol receptors and/or cortisol action but do not decrease 
439  cortisol levels, the following are recommended for subjects with glucocorticoid-induced 
440  hypertension: 
441   
442    SBP and DBP values should be measured by ambulatory blood pressure monitoring.  

443   
444    For the baseline assessment, mean SBP and mean DBP should be obtained within 1 to 

445  2 weeks before randomization for all subjects at baseline, followed by regular 
446  intervals. 
447   
448    For dose titration, mean SBP and/or mean DBP values obtained within 1 week of 
449  the titration visit should be used for dose titration.  
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450   
451    For the primary and secondary efficacy endpoints, mean blood pressure obtained 
452  within 1 week of the end of the fixed-dose period should be used. 
453   
454    For the secondary endpoint, changes in dose(s) and/or number of antihypertensive 
455  medications. 
456   
457  8.  Statistical Considerations 
458   
459    Trial protocols and statistical analysis plans should clearly prespecify the estimands of 
460  primary interest. The description of the estimands should reflect the clinical questions of 
461  interest in respect to thoughtfully envisioned intercurrent events.17 The statistical 
462  analyses should be aligned with the estimands of primary interest and clearly specify how 
463  intercurrent events and missing data will be accounted for. Sponsors should consult with 
464  FDA about these issues during the trial design stage. Sponsors should provide adequate 
465  justifications that the proposed estimands address meaningful clinical questions of 
466  interest and can be estimated with plausible assumptions. Refer to ICH E9(R1) for more 
467  discussions on estimands and intercurrent events. 
468   
469    If a noninferiority trial design is considered, sponsors should discuss with FDA the 
470  choice of the active control and noninferiority margin. FDA recommends that sponsors 
471  provide FDA with adequate justification in the protocol for their choice of noninferiority 
472  margin and seek FDAs agreement on that choice.18 
473   
474    Randomization of subjects should be stratified by UFC levels at baseline, country/region, 
475  and prior radiation therapy. In addition, in trials of drugs that block cortisol receptors 
476  and/or cortisol action but do not decrease cortisol levels, subjects assigned to the 
477  glucocorticoid-induced hyperglycemia subgroup should be stratified by diabetes versus 
478  impaired glucose tolerance.  
479   
480    Subjects who initiate rescue therapy for any reason and/or discontinue study treatment 
481  should continue trial participation and follow all planned visits and assessments until the 
482  end of the trial. 
483   
484    Missing data are measurements that are planned to be collected and used for estimating a 
485  target estimand but not available at the end of the trial. Missing data may occur because 
486  of withdrawal of informed consent for collection of additional data, missed clinical visits, 
487  and loss to follow-up. The existence of missing data increases uncertainty in estimation. 
 
17 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 (e.g., discontinuation of assigned 
treatment, use of prohibited medications, use of alternative or additional medications, corrective surgery). See the 
ICH guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity 
Analysis in Clinical Trials (May 2021). 
 
18 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016) (FDA 
Noninferiority Guidance). 
 
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488  The amount of missing data should be minimized. For operational measures to prevent 
489  missing data, refer to the National Academy of Sciences report on missing data.19 
490   
491    Despite the best precautions, some data will inevitably be missing. How the statistical 
492  analyses will account for missing data should be carefully prespecified in the statistical 
493  analysis plan. Missing data should be imputed with the corresponding uncertainty in a 
494  manner consistent with what the values would likely have been had they been collected. 
495  We generally recommend that missing data be multiply imputed using appropriate 
496  methods based on plausible assumptions. Rubins method can be used to combine the 
497  estimated treatment effects and variability across the multiple imputations. For 
498  noninferiority comparisons, an imputation under the noninferiority null approach should 
499  be considered per the FDA Noninferiority Guidance. 
500   
501    The imputation of missing data typically relies on some assumptions of missing 
502  mechanisms that are not verifiable. To assess the sensitivity of results to such uncertainty, 
503  sponsors should conduct sensitivity analyses, such as tipping point analyses, that vary 
504  assumptions about the missing data. The tipping point analyses should allow assumptions 
505  about the missing outcomes on the two treatment arms to vary independently and should 
506  also include scenarios where missing data on one treatment arm indicates worse 
507  outcomes than missing data on the other treatment arm. The goal is to evaluate the 
508  plausibility of the assumed expected values for missing outcomes on each treatment arm 
509  under which the conclusions change (i.e., under which there is no longer evidence of a 
510  treatment effect). For continuous data, we recommend centering the tipping point 
511  analysis around the analysis that most appropriately addresses missing data. 
512   
513    Supplementary analyses targeting different estimands may be useful to provide additional 
514  insights into the treatment effect, but they do not directly evaluate the missing data 
515  assumptions of the primary analysis. 
516   
517    The number of subjects in confirmatory trials should provide adequate power to evaluate 
518  the primary endpoint.    
519   
520    The primary analysis model should estimate the difference and its associated confidence 
521  intervals in rate of responders between treatment groups and should adjust for prognostic 
522  covariates as well as any variables used to stratify the randomization.  
523   
524    If statistical significance is achieved on the primary endpoint, the type I error rate should 
525  be controlled across all clinically relevant secondary efficacy endpoints intended for 
526  product labeling. 
527   
528    Graphical methods showing UFC values over time should be presented, and additional 
529  graphical presentations of the data to illustrate the effect of the drug are encouraged. For 
 
19 National Research Council, 2010, The Prevention and Treatment of Missing Data in Clinical Trials, Washington, 
DC: The National Academies Press. 
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530  examples, see the guidance for industry Clinical Studies Section of Labeling for Human 
531  Prescription Drug and Biological Products  Content and Format (January 2006). 
14