Fifty years ago North American oncologists defined 5 sequential phases in clinical cancer research, which are now used for the development of all new drugs. The clinical-medical investigator follows these 5 phases in the proper order, till the new drug eventually appears to be safe and effective. Only about 5% of all new drugs reach the finish, phase 4.
|0||Pre-clinical research||Translating new basic science into clinical applications by way of laboratory bench and experimental animal research.||31%|
|1||Toxicity/side effects||Determination optimal dose and method of administration in small and large animal research, sometimes in healthy human volunteers and eventually in end stage human patients.||7%
|2||Activity||Determination of the activity of a new drug in a small group of patients diagnosed with one specific form of cancer or a new treatment in a well defined group of patients with another –not cancer- disease or problem.||15%|
|3||Randomized trial||Double blind: new vs. existing therapy or placebo. Large numbers of patients studied in many institutions for log periods of time.||31%|
|4||Post-marketing analysis||Determine side effects of new drug after prolonged use and interactions with other medications.||16%|
- It takes too long, it is too expensive and it delivers too little of value.
- Not enough money available? No, this is not a money problem because developed countries spend between 6 and 15% of their Gross National Product on healthcare.
- Are the available funds well spent? No, not enough good drugs are discovered. For various reasons the new drugs, that complete all the drug development phases, are expensive, not very effective and often cause serious side effects.
- Large sums of money end up in what patients often call -and for good reasons- ‘the wrong pockets’, like the pharmaceutical industry, health insurance organizations and CEOs of hospitals.
% of medication that does not reach the research finish line
For two reasons:
- The pharmaceutical industry demands that the prices of new drugs are allowed to be higher than the production costs of the drugs. Not higher by a small margin, but 10-100 times more, by including the development costs of the 95% of new drugs that do not reach the finish-line.
- The utilization of what in P2T’s opinion is questionable research methodology, so-called ‘Evidence based medicine’. The best, level 1, proof, that a new treatment or a new diagnostic test is a valuable addition to the existing panel of drugs, would be a double blind randomized phase 2 or 3 study.
Academic ethicists and statisticians demand randomized phase 3 trials between two new drugs or between a drug and a placebo. Such studies need to be continued till one arm of the study is better than the other arm with a Probability value, p-value, of less than 0.05. In addition the two study arms need to provide ‘equipoise’ to patients: similar risks for beneficence and side effects. Those demands can only be met by entering hundreds of patients in each arm. This will increase the number of institutions that need to participate in the study and escalate study duration and costs. The best arm is the drug with the fewest side effects and the best therapeutic results. Due to equipoise the two arms have similar low efficacy. Usually less than 1 of 5 patients in the ‘best’ study arm benefits from this drug.
Another compelling reason to perform randomized double blind phase 2 and 3 studies is that the Food and Drug administration in the United States will only allow the Pharmaceutical industry to market a new drug if it performs well in at least 2 phase 3 studies. Fortunately the European Medical Association and the World Medical Association are not convinced that double blind randomized phase 2 or 3 studies are necessary or that placebo arms are necessary or ethically justifiable. EMA and WMA prefer single arm phase 2 studies.
Evidence based medicine is not ‘cookbook medicine’. Some questions about therapy do not require randomized trials (successful interventions for otherwise fatal conditions). We must follow the trail to the next best external evidence and work from there.
P2T advocates a radically different approach, which lowers costs and shortens the development of new drugs and treatment methods. We help independent clinical-medical investigators to perform phase 2 studies. Objectively and quantitatively and above all: not-for-profit.