FDA issues draft guidance on developing drugs for acromegaly

The US Food and Drug Administration (FDA) has issued a draft guidance to assist sponsors develop acromegaly treatments for patients who have either not responded to surgery or are in poor health.
 
Acromegaly is a chronic, rare disease in adults caused by excess growth hormone that can cause enlarged hands and feet, among other symptoms. The most common cause stems from a growth hormone that stimulates hepatic overproduction of insulin-like growth factor-1 (IGF-1).
 
Current FDA-approved treatments for acromegaly include drugs from several pharmacological classes including somatostatin analogs (octreotide, lanreotide, and pasireotide), a GH-receptor antagonist (pegvisomant), and a dopamine-receptor agonist (bromocriptine).  
 
The guidance “is intended to serve as a focus for continued discussions among the FDA Division of General Endocrinology, pharmaceutical sponsors, the academic community, and the public,” according to the Federal Register announcement.
 
“The goal of medical therapy is to normalize IGF-1 levels for age and sex and to decrease random [growth hormone] levels below 1 mcg/L,” the draft guidance states.
 
The draft guidance covers general considerations for studies of acromegaly therapeutics, as well as specific considerations for the design of Phase 3 studies, including eligibility criteria, efficacy assessment, safety considerations, and statistical considerations.
 
Professional societies recommend medical therapy for patients with persistent or recurrent disease despite surgery, those who are waiting for radiotherapy to lower IGF-1 levels, and those who are not candidates for surgery due to poor health, the draft guidance notes. 
 
FDA said assessing a drug’s efficacy may be challenging as “many acromegaly symptoms are nonspecific (e.g., headache, fatigue, sweating) and may be related to concomitant medical conditions (e.g., hypertension, diabetes) or medications.” The guidance adds that these factors also “may make it challenging to show that the drug improves symptoms.”
 
To show improvement of symptoms, FDA recommends that sponsors used fit-for-purpose, patient-reported outcomes that assess the signs and symptoms of acromegaly. The draft guidance notes that “nonvalidated patient-reported outcomes should not be included as primary or key secondary efficacy endpoints and are appropriate as exploratory endpoints only.”
 
FDA says that sponsors should also specify and justify the estimands in study protocols and statistical analysis. Sponsors should consult the International Council on Harmonization’s (ICH) E9(R1) addendum on estimands and sensitivity analysis for more information on their use in clinical trials.
 
To assess safety, sponsors should monitor pituitary tumor size, assess injection site reactions, evaluate hypersensitivity reactions, and gastrointestinal adverse events.
 
The deadline for commenting is 31 March. Submit comments here.
 
Draft guidance