Randomized Start Design (RSD)

FDA recently issued its guidance "Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease ". The guidance cited alternative trial designs and the Randomized Start Design (RSD) was recommended.

A randomized-start or randomized-withdrawal trial design (with clinical outcome measures) appears to be a more convincing means of demonstrating such an effect. For ethical reasons, a randomized-start design would be most appropriate for use in AD. In this study design, patients are randomized to drug and placebo, and at some point, placebo patients are crossed over to active treatment. If patients in the trial who were initially on placebo then assigned to active treatment fail to catch up (after a reasonable period of time) to patients who received active treatment for the entire duration of the trial, a disease modifying effect of treatment would have been shown. We are unaware of any instances to date where this design has been successfully used in a clinical trial to establish a disease modifying effect.

RSD has been discussed for its use in many CNS and neurological diseases such as Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, Post Polio syndrome. These diseases all have very slow progression. Treatment effect for these diseases can be separated as effect on symptomatic component and the disease modifying component.  "Disease modifying" can be defined as treatments or interventions that affect the underlying pathophysiology of the disease and have a beneficial outcome on the course of the disease.

A similar design to RSD may be called "delayed start design". The delayed-start design is used in order to overcome a problem that occurs in similar studies of medicines that may slow the progression of the disease but also have an effect on symptoms. Typically in these studies used to determine the effects of a drug on slowing disease progression, the medicines or placebo are started and stopped in all patients at the same time. After stopping the drugs, the researchers then wait for several weeks to measure the patients’ symptoms. This waiting time is referred to as the “washout” period, in which the effects of the drug are “washed out” of the body. Patients whose symptoms remain better at the end of the washout period time are presumed to have had their disease slowed by the treatment. However, no one knows what length of time is needed for a true symptomatic washout period. When a study uses a delayed-start design, all patients are presumed to be experiencing the same degree of symptom relief at the end of the trial because they are all taking the medication. If the patients who have received the medicine for the longer period of time have fewer symptoms, it is presumed to be due to the medicine slowing the effects of the disease.

Further reading:

·  The Randomized Start Design for Assessing Disease-Modifying Effects in ParkinsonDisease: Issues and Controversies by David Oakes

·  Designing clinical trials to test disease-modifying agents—application to the treatment trials of Alzheimer's disease by Xiong

·  A new proposal for randomized start design to investigate disease-modifying therapies for Alzheimer disease by Zhang

A New Drug Approval Pathway - Breakthrough Therapy Designation

Recently, a new drug approval pathway proposed by FDA has drawn attentions to many pharmaceutical/biotechnology companies. Last year, The Food and Drug Administration Safety and Innovation Act (FDASIA) included a provision that allows sponsors to request that their drug be designated as a Breakthrough Therapy. Breakthrough status means the companies will have closer communication with top FDA staff to move drugs for serious diseases to market more quickly, potentially with data from an expanded Phase 1 trial.

• US FDA announces first Breakthrough Therapy Designations
• Innovative Drugs May Win U.S. Approval After Early Trials- Novartis grabs FDA's coveted 'breakthrough' status for lung cancer drug
• Pharmacyclics Gains ‘Breakthrough’ Status for Cancer Drug
• Pfizer's Palbociclib Receives Breakthrough Therapy Designation for Breast Cancer Treatment

Only a small portion of drugs can obtain the Breakthrough Therapy designation. The drugs for treating the serious diseases with unmet medical needs may be easier to obtain the Breakthrough status. The drugs targeting the small sub-population of certain disease may also be qualified for Breakthrough Therapy designation (see the example for Vertex' Kalydeco). The clinical trial that designed to target the small sub-population is called enrichment clinical trial design (i.e., choosing sub-population that is likely to respond to the study drug, therefore design a smaller study) . See recent FDA guidance.

Only a small portion of drugs can obtain the Breakthrough Therapy designation. The drugs for treating the serious disease with unmet medical needs may be easier to obtain the Breakthrough status. The drugs targeting the small sub-population of certain disease may also be qualified for Breakthrough Therapy designation (see the example for Vertex' Kalydeco). The clinical trial that designed to target the small sub-population is called enrichment clinical trial design (i.e., choosing sub-population that is likely to respond to the study drug, therefore design a smaller study) . See

recent FDA guidance.

FDA Existing Drug Approval Pathways are:

• Accelerated approval for serious disease with unmet medical need. Approval with surrogate endpoint with commitment for confirmatory trial with clinical endpoint.
• Orphan drug status or orphan drug designation for rare diseases
• Restricted distribution Approval with restrictions to assure safe use
• Priority review FDA completes review within 6 months versus standard review time of 10 months
• Fast track review to facilitate the development, and expedite the review of drugs to treat serious diseases and fill an unmet medical need
• Breakthrough drug designation see above
• the Generating Antibiotics Incentives Now (GAIN) Act. For antibiotics

In addition, there is a movement for Patient oriented drug development (i.e., the study endpoint should measure ‘feel, function, or survival’ of the patients). See

FDA presentations on this topic.

In EU, the Adaptive Licensing is gaining more interests. The idea of Adaptive Licensing is to allow a drug to be launched onto the market with certain restrictions, based on its benefit/risk profile. Those restrictions could then be gradually removed as more positive data is forthcoming and more favorable benefit/risk profile. However, in US, there is no movement about Adaptive Licensing isea.  

Attached is FDA's Development & Approval Process (Drugs)

•  How Drugs are Developed and Approved
•  Drug and Biologic Approval Reports
•  NDA and BLA Approvals 
•  NME Drug and New Biologic Approvals
•  ANDA (Generic) Drug Approvals
•  Priority NDA and BLA Approvals
•  Efficacy Supplement Approvals
•  Accelerated and Restricted Approvals 
•  NDA Approvals by Therapeutic Potential and Chemical Type
•  Fast Track Approval Reports