Rethinking Clinical Trial Designs for ALS to Increase Access and Shorten Duration

Clinical trials are a great way for people with no treatments options to try experimental drugs, therapies, and devices.  They help researchers weed out promising treatments from those who prove not to be safe or effective.  The classical clinical trial design starts by randomly selecting out two groups of participants for the study, one called the treatment or intervention arm and one called the placebo or control group.  Because there are so many factors that are difficult to control for in a statistical analysis such as normal rate of decline among each participant, types of ALS (familial versus sporadic and bulbar versus limb-onset), and unknown factors that cannot be calculated, placebo or control groups are put in place so that researchers can determine actual effects of the drug, treatment, or device.  In other words, to measure a drug’s effect you need a comparison group.  Otherwise you’ll never know if the drug is having the effect on ALS or something else in the person’s body or environment.

There are typically three phases to clinical trials. Phase 1 studies are done to determine whether or not a drug is safe and to determine a safe dose for further testing.  Phase 2 studies determine biologic activity, is there a positive effect on disease measures.  Phase 3 studies determine efficacy.  This process is expensive and arduous.  To start a clinical trial, the company must first file a Research IND with the U.S. FDA, which includes a written study protocol and previous animal or cell based research showing there will not be unreasonable harm to participants.  Clinical sites must be recruited, databases created and drug supplies distributed.  At best it takes a year to mount a trial.  Add on another year when considering the time it takes to apply and receive publically funded grants.  Clinical trial barriers therefore can be summarized by time, funding, capacity, and design.   

A major point of discussion relevant today is clinical trial designs and goals.  Researchers and industry running the clinical trials must consider feasibility of conducting the trial.  That is what are their staff, facility, and manufacturing capabilities and cost of conducting the trial.  Whereas, clinical trial goals for someone with ALS include early (faster) drug development and more opportunities to try experimental drugs and treatments.  The solution to these competing goals would appear to lie within changing the standard clinical trial design to either include more participants and/or speed up the process.

There is certainly precedence for this in the published literature.  Dr. David Byar, a statistician, in 1990 offered clinical design solutions for HIV/AIDS research, which revolutionized how we approach clinical trials research.  Gehen (1986),  Schoenfeld (2005), Schoenfeld and Cudkowicz (2008) also analyzes different designs in cancer and ALS.  Here are a few options.

• Futility design: This design is intended to speed drug development.  If shown to possibly work, then it proceeds to further studies.  In this design the null and alternative hypotheses are reversed such that the objective of the study is to prove that a drug DOES NOT work (versus typical clinical study designs where drugs have to be proven to work).  This design has good sensitivity but poor specificity.  This means that it does well at finding drugs that are effective but does not do well at finding drugs that are ineffective.  According to Schoenfeld and Cudkowicz (2008) this design could be run as a phase 3 trial with a placebo or control group and increased numbers of participants or could be run without a placebo or control group but reduced numbers of participants.  
• Lead-in design: In this design participants are followed for a 3-month period to measure average rate of decline, then treated for 6-months with a follow-up period.  This design could eliminate the need for a placebo or control group because each participant becomes his or her own control for the lead-in time.  Or a historical control could be used if assumed that there are no differences in average rates of decline by time.  Lead-in designs can also allow a researcher to decrease the number of participants needed in the study.  By decreasing the number of participants, however the final analysis must assume that someone’s average rate of decline in the 3-month period before treatment will be the same throughout the study (non-robust analysis).  In the robust or conservative analysis that does not assume a consistent rate of decline throughout the study period the number of participants would not be reduced.
• Two-stage design: The purpose of this design is to speed up the trial process by combining two drug development stages into one study.     
• More flexible entry criteria:  Byar et al (1990) argues that if treatments are found to be effective in clinical trials are likely to be offered to most patients, most patients should be eligible to enter the trials and the exclusion criteria should be systematically relaxed in order to reach this goal.  The reason clinical trials have restrictive entry is so treatment effects can be measured more precisely.  However using a method known as stratification you can analyze treatment effect based on subgroups (e.g. familial ALS versus sporadic ALS, bulbar versus limb-onset ALS).  This analysis becomes more robust with larger number of participants.        

Albert Einstein once said, “A system is only as good as its design.”  When we think about clinical trials there is no perfect study or ‘gold standard.’  Each available study design has its pros and cons.  It usually comes down to a calculation of what errors are researchers willing to accept at what cost. 

In statistics and epidemiology classes we learn that the higher your sample size or number of participants in your study, the less error or study bias you will have.  Each person you include in a study however increases the overall cost.  This is why most companies, particularly start ups have the goal of including the least number of participants at the cost of statistical power.  That is, studies with small numbers lose the ability to say with greater accuracy whether or not an effect they are seeing is true.  This is why drugs might appear safe and effective in Phase 1 and 2 trials, but bomb in Phase 3.

Now is the time to reconsider clinical trial designs for people with ALS.  The ALS Association is looking to put together a guidance document for the FDA on among many things, clinical trial design. 

Tell the U.S. FDA and industry that you want more options to try experimental drugs and faster clinical trial processes through futility designs in Phase 1, two-stage designs in Phase I/Phase 2 and Phase 2/Phase 3, relaxed entry criteria, increased sample size, and lead-in designs.  Ask policymakers to increase funding and work with industry to eliminate barriers to increasing sample sizes.    

        

References

Byar et al (1990).  Design Considerations for AIDS Trials.  New England Journal of Medicine, 323(19), 1343-1347.

Schoenfeld and Cudkowicz (2008).  Design of Phase II ALS clinical trials.  Amylotrophic Lateral Sclerosis, 9: 16-23.