Disease-Specific Drug Development Guidances Coming From US FDA In 2018

Alzheimer's disease, amyotrophic lateral sclerosis, migraine, and opioid dependence are among conditions that will get drug development guides from FDA; other guidances will address ANDA bioequivalence studies, shared REMS, and continuous manufacturing.

The US FDA's guidance to-do list for the year has a unique focus on development of drugs for specific diseases. The lineup includes guidances targeting six diseases, including early Alzheimer's disease, amyotrophic lateral sclerosis, migraine and opioid dependence.

FDA Commissioner Scott Gottlieb announced at a meeting in September that the agency would begin work on new disease specific development guidance documents over the next year. (Also see "FDA's Gottlieb Pushing 'Seamless' Clinical Trials For Faster Development" - Pink Sheet, 11 Sep, 2017.)

Gottlieb has said that the guidance-writing initiative is intended to articulate modern evidentiary and clinical trial design expectations in disease areas where the science has evolved. He noted that the goal is to create more incentives for people to target unmet medical needs. (Also see "Alzheimer's Guidance Coming From US FDA, Part Of Broader OND Reform" - Pink Sheet, 14 Sep, 2017.)

In addition to the guidances on developing drugs, one focuses on antiepileptic drugs for treatment of partial onset seizures and the extrapolation of efficacy from adult to pediatric patients.

Updated Agenda Removes Some Guidances

The Center for Drug Evaluation and Research's previous guidance agenda for calendar year 2018, released Jan. 19, lays out a list of 10 disease-specific guidances targeted for publication, a total in line with Gottlieb's comments on the effort this fall. However, later that day, the agency released an updated guidance agenda, saying the first version had been released in error. The updated agenda cuts the number of disease-specific guidances to six and makes other revisions to the list.

The drug-specific guidances removed in the updated agenda were:

• BCG-unresponsive non-muscle  invasive  bladder cancer: developing  drugs and biologics for treatment,
• Duchenne muscular  dystrophy  and related dystrophinopathies: developing  drugs for treatment,
• Exocrine  pancreatic  insufficiency   drug  products:  submitting   marketing   applications and recommendations  for labeling (revised draft),
•  Establishing effectiveness of drugs intended to treat male hypogonadotropic hypogonadism attributed to non-structural disorders, and
• Gaucher disease: drug development  considerations  including  a multi-company, multi-arm, controlled trial – a collaborative approach for drug development  in  pediatric rare disease

The hypogonadotropic hypogonadism guidance and Gaucher guidance were already released by FDA, so removing them from the updated agenda makes sense. (Also see "US FDA's New Hypogonadism Guidance Focuses On Non-Testosterone Products" - Pink Sheet, 4 Jan, 2018.) and (Also see "How To Conduct A Multi-Company Trial For Rare Pediatric Diseases" - Pink Sheet, 6 Dec, 2017.)

For other conditions, FDA's decision to remove guidances from the list suggests the agency has considerably more work to do in setting standards on product development.

In Duchenne muscular dystrophy, for example, FDA issued draft guidance in 2015 (Also see "Duchenne Muscular Dystrophy: FDA Supports Broader Outcome Measures, Biomarkers" - Pink Sheet, 10 Jun, 2015.) So while one might expect a final guidance at some point, the subsequent review controversies surrounding products likely mean that the guidance is subject to considerable attention from agency leadership.

Another guidance that was dropped from the list was "Opioid Dependence: Endpoints for Establishing Effectiveness of Medically Assisted Treatment (MAT) Drugs," an interesting elimination given that Gottlieb has emphasized the need for greater acceptance of these products. (Also see " Addiction Recovery Medications' 'Stigma' Needs To Be Eliminated, Gottlieb Says" - Pink Sheet, 25 Oct, 2017.) A guidance on developing depot buprenorphine products for treatment of opioid addiction remains in the updated agenda. (Also see "Opioid Treatments Could Get Survival Claim As US FDA Develops Protocol" - Pink Sheet, 1 Dec, 2017.)

A guidance on streamling developments of pediatric HIV drugs intended for global use was added in the updated agenda, but for the most part the document removes guidances from FDA's target list for the year. The agency is no longer projecting it will issue guidance on a streamlined submission process for companion diagnostics in oncology trials this year. And industry isn't scheduled to get an advice document on refuse to file for NDAs or BLAs because it came out last year (Also see "Refuse-to-File Turns 25: New Guidance Changes In Style, But Not Substance" - Pink Sheet, 11 Jan, 2018.)

Two guidances related to pregnancy issues were eliminated in the updated agenda: revised drafts are no longer expected on the design, data analysis and labeling related to clinical lactation trials or pharmacokinetics during pregnancy and the postpartum period.

New Topics And Holdovers

Overall, the agenda lists topics for new and revised draft guidances planned for publication this year that include adaptive design clinical trials, biomarker qualification, shared Risk Evaluation and Mitigation Strategies, and continuous manufacturing. (See chart below.)

Several of the items are holdovers from CDER's 2017 guidance agenda, including guidances on meta-analysis of randomized controlled clinical trials to evaluate the safety of human drugs or biological products; in-vitro methods for evaluation of abuse deterrent properties of opioid products; public disclosure of FDA-sponsored studies; REMS assessment: planning and reporting; and user fee waivers, reductions, and refunds for drug and biological products.

FDA issued one of the draft guidances on the list the day before FDA posted the agenda. That document is "Product Title and Initial U.S. Approval in the Highlights of Prescribing Information for Human Prescription Drug and Biological Products – Content and Format."

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2018 Guidance Agenda
Below are some of the new and revised draft guidances the Center for Drug Evaluation and Research plans to publish this year.
Category	Title/Background
Advertising	Presenting quantitative information in direct-to-consumer promotional labeling and advertisements FDA's Office of Prescription Drug Promotion is conducting a study on quantitative information in DTC television ads to examine whether consumers can take more complicated information into account when assessing Rx drug information in these ads (Also see "DTC Rx Drug Ad Study No. 30: Do Market Claims Impact Perception?" - Pink Sheet, 29 Jul, 2015.)
Clinical/Antimicrobial	Developing drugs for treatment and prevention of cytomegalovirus in transplantation
Clinical/Antimicrobial	Developing antimicrobial drugs for treatment of uncomplicated urinary tract infections Candidates are in the pipeline for this indication (Also see "Antibiotic Pipeline Profile: Balancing Broad Spectrum And Limited Use" - Scrip, 5 Jul, 2017.)
Clinical/Medical	Developing drugs for treatment of amyotrophic lateral sclerosis
Clinical/Medical	Developing drugs for early Alzheimer's disease
Clinical/Medical	Developing fixed-dose combination drugs for treatment of hypertension
Clinical/Medical	Developing drugs for treatment of migraine
Clinical/Medical	Developing depot buprenorphine products for treatment of opioid dependence
Clinical/Medical	Pediatric oncology product development FDA's Oncology Center of Excellence noted that development of pediatric cancer therapeutics and diagnostics would be a key focus (Also see "Pediatric Drug Development A Priority For US FDA’s New Oncology Center Of Excellence" - Pink Sheet, 22 Feb, 2017.)
Clinical/Statistical	Adaptive design clinical trials for drugs and biologics; revised draft
Clinical/Statistical	Meta-analysis of randomized controlled clinical trials to evaluate the safety of human drugs or biologic products FDA noted in May that the guidance is awaiting clearance (Also see "Woodcock Wants Rapid Regulatory Policy Development" - Pink Sheet, 22 May, 2017.)
Drug Development Tools	Biomarker Qualification: Evidentiary framework FDA has qualified several new biomarkers for use in clinical trials through the Biomarker Qualification Program (Also see "US FDA Progress Report Highlights Biomarkers, Continuous Manufacturing, Antibiotic Testing" - Pink Sheet, 30 Mar, 2017.)
Drug Safety	Postmarketing safety reporting for human drugs and biological products including vaccines; revised draft
Generics	Bioequivalence studies with pharmacokinetic endpoints for drug products submitted in ANDAs; revised draft
Generics	Failure to timely respond to an ANDA CR letter Office of Generic Drugs Director Kathleen Uhl noted common reasons ANDAs are rejected (Also see "Want To Avoid A Refuse-To-File? Submit ANDA In English, FDA Says" - Pink Sheet, 3 Jan, 2018.)
Pharmaceutical Quality/CMC	In-vitro methods for evaluation of abuse deterrent properties of opioid products
Pharmaceutical Quality/CMC	Quality considerations for continuous manufacturing CDER's Emerging Technology Team has been helping industry transition from batch to continuous manufacturing methodologies (Also see "FDA Ushers In Era of New Drug Manufacturing Technologies" - Pink Sheet, 20 Jun, 2016.)
Procedural	Citizen petitions and petitions for stay of action subject to Section 505(q) of the federal Food, Drug, and Cosmetic Act
Procedural	Development of a shared system REMS
Procedural	Waivers of the single, shared system REMS requirement Speaking at an FTC workshop on competition in prescription drug markets, FDA Commissioner Scot Gottlieb said a waiver could prevent brand name companies from using negotiations over a shared REMS to slow generic entry (Also see "REMS Barriers: US FDA Takes 'Foundational Step' To Improve Generic Access" - Pink Sheet, 8 Nov, 2017.)
Rare diseases	Rare diseases: common issues in drug development
User fees	Prescription Drug User Fee Act waivers, reductions, and refunds for drugs and biological products