Pharma to FDA: Limit or Spell Out Use of Covariates in Randomized Trials

July 1, 2019

The FDA should limit or at least spell out the different kinds of covariates allowed in randomized trials, a pair of drug industry giants told the agency.

In comments on the FDA’s April draft guidance on adjusting for covariates in randomized trials, AstraZeneca and LabCorp urged the agency to consider just how much might be too much when using complicated covariance analysis to help determine statistical significances or to help sharpen estimates of how well a treatment might work.

AstraZeneca said it worries that too “many prognostic factors could result in overfitting,” which could lead to faulty conclusions.

LabCorp urged “caution” when thinking about covariates in small sample sizes, for similar reasons that AstraZeneca cited. The network also suggested that regulators include a discussion on what’s to be done when covariates are missing data.

Read the draft guidance and the four comments here:

FDA Seeks Comment on ICH Safety Data, Bioanalytical Validation Guidances

The FDA is inviting public comment on two International Council for Harmonisation draft guidance documents, one designed to help move clinical trials along more quickly, the other designed to make sure that researchers are getting the best possible data before trials can get started.

In ICH E19 — Optimization of Safety Data Collection, the ICH asks whether some safety data can be trimmed from trials in order give patients a break from near-endless recordkeeping. The council is interested in learning how some safety data could be cut out of trials.

Separately, in ICH M10 — Bioanalytical Method Validation, the council has issued draft guidelines on how researchers can validate their bioanalytical assays in nonclinical trials.

Comments on both draft guidances are due by Sept. 25.

Read the E19 guidance here:

Read the M10 guidance here:

FDA Considers How Heart Patients Feel, Function, in New Draft Guidance

Endpoints for heart failure drug trials could be based on improvements in subjects’ symptoms and/or daily life, not just their survival, under a new draft guidance the FDA released last week.

“A drug that improves symptoms or function when added to standard of care would be valuable even if it did not improve survival or hospitalization,” the 10-page draft guidance says. “Moreover, it is possible that if a drug provided substantial and persistent improvement in symptoms or function … some decrease in survival would be acceptable.”

If sponsors want to take the quality-over-mortality path, the agency would consider such factors as:

  • The mortality and other safety findings for similar drugs;
  • The amount of time patients will be exposed to a candidate drug, such as a treatment of fewer than 10 days, which carries no requirement for long-term mortality data; and
  • Mortality and safety data on the candidate drug for a closely related population.

Read the draft guidance here:

FDA to Require Clinical Data for High-Risk Tissue Ablation Systems

Sponsors of certain high-risk prostate tissue ablation systems would have to collect additional clinical data to support their applications for FDA clearance under a draft guidance issued by the agency last week.

High-intensity ultrasound tissue ablations systems are considered “significant risk” devices, the draft guidance says, a classification that imposes additional requirements for clinical testing to document the device’s adverse event profile and provide evidence of efficacy.

“Prostate tissue ablation devices addressed by this guidance document are significant risk devices subject to all requirements of the Investigational Device Exemptions (IDE) regulation,” the guidance says. Sponsors of such devices also would be required to follow clinical trial regulations governing IRB review and informed consent.

Recommended safety and efficacy endpoints should include determination that the device:

  • Does not damage tissue outside the target range; and
  • Does ablate tissue within the target range.

The guidance also would allow, in some cases, real-world data to support energy output changes to a device that already has obtained 510(k) clearance.

Comments on the draft guidance are due Aug. 26.

Read the draft guidance here:

FDA Issues Guidance on Developing Drugs to Treat Epidermolysis Bullosa

Sponsors of drugs to treat or prevent serious flare-ups of certain skin disorders are allowed to use endpoints based on symptom relief under a final guidance from the FDA.

There is insufficient clinical experience to establish definitive endpoints for treatment of epidermolysis bullosa, the guidance says, but trials may collect data on effects on symptoms such as itching, pain, blister prevention, and wound healing.

Before beginning a trial, the agency recommends sponsors discuss with the review division the choice of the primary efficacy endpoints and the time point for evaluation.

The guidance notes that recruitment and retention of patients with certain types of EB is challenging because trial procedures can exacerbate skin damage. Special considerations for this may include telemedicine and other avenues to reduce the need for patient travel.

Read the full guidance here:

FDA Plans 2019 Draft Guidances on Trial Designs, Gene Therapies

The FDA’s Center for Biologics Evaluation and Research has released its guidance agenda for the second half of 2019, including planned draft guidances on trial designs and several gene therapies.

In its guidance agenda for the remainder of the year, CBER lists a draft guidance for sponsors on working with the FDA to design complex and innovative trials for drug and biologic products.

The list also includes plans for draft guidances on the study of human gene therapies for hemophilia, retinal disorders and rare diseases.

The guidance agenda does not guarantee that CBER will address all topics on the list and does not preclude the center from developing guidance documents on subjects not on the list.

Read the CBER guidance agenda here:

FDA Rethinking Trial Data Transparency Pilot

The FDA is turning to the public to help decide whether it should continue its languishing program to share trial data on approved drugs.

Launched in 2018, the agency’s plan was to enroll nine drug sponsors in a pilot program to test the feasibility of releasing sponsor-generated summaries of trial methods and results. In March 2018 the pilot produced a single data summary report and has shown no activity since then (CenterWatch, January 21, 2019).

In a Federal Register notice last week, the FDA invited drug companies and other interested parties to weigh in on the future of the pilot program. The agency said it wants to hear from drug companies about their concerns and suggestions for improving the program enough to attract more participants.

At the same time, it asks for comments on whether to scrap the pilot and focus on a new review template for drug sponsors. The template proposed would summarize expert views on a drug’s safety and efficacy instead of having reviewers comment individually.

Comments are due by Aug. 26.

Read the notice here:

AbbVie to Acquire Allergan in Seismic $63 Billion Deal

AbbVie sent shockwaves through the drug industry last week, announcing that it had reached a deal to acquire fellow drug giant Allergan for approximately $63 billion.

The deal will bring Allergan and its blockbuster Botox under AbbVie’s roof, giving AbbVie some security as the exclusivity for rheumatoid arthritis blockbuster Humira nears its 2023 expiration. Humira earned global sales of almost $20 billion in 2018, while Botox earned $3.6 billion.

The deal is subject to federal review, but it’s roughly half of what was on offer three years ago, when Pfizer walked away from a proposed $160 billion takeover of Allergan.

Allergan President and CEO Brett Saunders will join AbbVie’s board under the terms of the transaction.