In an earlier post, I wrote about the challenges regarding animal trials in bringing drugs to market. Once a drug has passed the animal trials, there are still many challenges with human testing that contribute to the eye-popping average cost of drug development: $1.2 billion over 15 years.
For starters, drug testing on humans classically passes through four phases, as defined by US Food and Drug Administration:
Phase I: Safety — What is safe dosage range?
Phase II: Efficacy — Does the drug work?
Phase III: Efficiency — Does the drug work better than existing drugs for same purpose?
Phase IV: Toxicity — What are long-term effects? (Usually done after drug has gone to market)
Each of these phases can take several months or even years. Why? Each phase requires recruitment of test volunteers, trial design and its approval by an Independent Review Board (IRB), the testing itself, and (usually) a “washout” period to totally eliminate the tested drug from the test subject.
In addition to the time to get through these phases (and win approval from FDA), testing on drugs for Parkinson’s has several challenges specific to PD:
—Measurement: There is no objective scale (e.g., like blood sugar for diabetes) for PD. If you get 5% improvement, is that good or insignificant? And 5% of what? Since there is no objective scale, there is no “zero”. The “floor” of measuring trial success will vary from one trial to another. This is why finding biomarkers for PD is so critical.
—Progressive disease: Since PD is a progressive disease that goes on for years, ideally, you should be testing drugs over a long period. Testing toxicity becomes a particular concern if you are going to be taking a drug for (say) twenty years. But even a six-month trial is an expensive trial design.
—Placebo effect: A good trial design has a “control” (placebo) to rule out the placebo effect. However, the placebo effect for PD is particularly distorting. Why? The anticipation and novelty of being in a drug trial causes the patient to….generate dopamine! Dr. Christopher Goetz from Rush University Medical Center reviewed placebo effect in 11 studies and found that at least 16% of placebo patients got better despite not having the real drug. He said, “My patients tell me they feel better just walking into my office!”
—Heterogeneity: PD is incredibly hetereogeneic. That is one of those $10 medical words meaning PD has wildly different symptoms, progress, outcomes, depending on who you’re testing. So, for example, say the drug reduces tremors for one person…but the next person never had tremors as a symptom. Is the drug a success?
—Recruitment: The Michael J. Fox Foundation estimates that globally, between 40% and 70% of PD trials face delays because of a lack of volunteers. Recruitment for Parkinson’s has (in my opinion) been hampered by the disease being a low visibility disorder with extremely fractured advocacy organizations. In place of, say, the American Cancer Society, PD is represented by half a dozen national organizations. I suspect that recruitment is also hampered by the fact that PD is (primarily) a disease of people over 60, who may be less able to volunteer.
The medical community is aware of the need to reduce the excruciatingly long period to bring PD drugs to market. As Dr. Cristina Sampaio, Chief Clinical Officer of the CHDI Foundation, put it, “We need to forget everything we’ve learned about trial design and start all over again with trial design. We have to invent the wheel.”
One of the goals of the Michael J. Fox Foundation is to speed up PD research. The Foundation has created “Fox Trial Finder” so Persons With Parkinsons can more readily volunteer for research and be matched up with appropriate trials. A similar registry specific to Washington State has been set up via the University of Washington and the US Department of Veterans Affairs.
Another strategy of the Michael J. Fox Foundation is to make clinical trial management more efficient so grant recipients can stay focused on research. Based on the experience of conducting over 50 clinical trials, the Foundation has created a Clinical Strategies Team to work with grant recipients to optimize trial design, budgeting, contracting, and other aspects of clinical trial management.