Much of what we discuss here on Signals is what’s going on in the lab. I’ve definitely done my share of promoting basic science research in the cancer stem cell field (here and here). By now you, and almost everyone else, must be wondering why these “wonder drugs” aren’t being used yet. Well, it turns out that taking a drug from the lab bench and giving it to a patient is not quite as straightforward as we might think: welcome to the world of clinical trials and drug approval.
While experiments done in the laboratory are essential to new drug discovery, their findings are extremely limited in the application to human cancer patients. A drug may perform amazingly well in non-human, laboratory models, exemplifying “promising results for cancer treatment,” but this does not guarantee that it will have the same effectiveness in humans. As well, there are a number of questions still to be answered: how do we deliver it; how much do we give; how often, and for how long; does it interact with other drugs or food? And, most importantly, we have no information on the drug’s safety: its toxicity and possible side effects in humans. The clinical trial process is used to answer these questions sequentially.
Once researchers have identified a promising new drug in their laboratory, they are able to apply for clinical trial approval. In Canada, Health Canada (Health Products and Food Branch) will review the preclinical trial data (i.e. the laboratory findings) for drug efficacy and toxicity in the non-human models used by the researchers. If the data is favourable, the researchers will receive approval for commencing clinical trials. I should also mention that the application involves extensive planning of the trials as well, including descriptions of the patient selection process, patient monitoring, clinical staff, drug administration protocols, etc.
Clinical trials are performed in progressive stages known as ‘Phases’ – 0 through IV, with I-III being the most important (and discussed here) – in order to address all concerns of drug safety and performance in humans. The Canadian Cancer Society has a nice overview; see here for more technical detail. Also check out my infographic on the topic for a visual explanation.
Phase I through III trials are the crux of the clinical trial process, and are required for drug approval. They address drug safety and dosing (I), drug effectiveness (II), and compare the new drug to existing therapies (III). Without successful completion of the previous phase, a drug cannot progress to the next phase of trials. This method prevents toxic and unsafe drugs from progressing too far.
As these phases progress, they become larger (more participants), and longer (in order to recruit patients, and monitor for side effects). As a result of being larger and longer, they become progressively more expensive to run, requiring a substantial amount of funding.
After successful completion of Phase III trials, researchers can begin the drug approval process to make their drug available to Canadians. At this point, 10-15 years may have gone by since the initial preclinical studies were performed. This is standard, due to the necessary rigor of the clinical trial process, not because researchers are trying to delay drugs getting to the patients who need them (for the conspiracy theorists out there).
Imagine that our researchers have completed Phase III trials for their new cancer drug; now begins the drug approval process.
Researchers apply for a New Drug Submission with Health Canada, where its Health Products and Food Branch will review the drug safety and efficacy data obtained from the clinical trials to determine if the benefits of the drug outweigh its risks. Drugs that are found to be better than the current standard of treatment (i.e. Phase III trial data) are more likely to be approved. When a drug is officially approved, it is now available for market in Canada, meaning that patients here can access the drug. To maintain approved status, drugs are subjected to mandatory adverse event monitoring/reporting, and adhere to strict manufacturing and distribution regulations.
Approved cancer drugs are then assessed by the pan-Canadian Oncology Drug Review (pCODR). While Health Canada approves the marketing of a drug, this group recommends whether or not the drug should be covered by the provincial health plans (i.e. OHIP in Ontario). This process takes into account the economics of the drug, with comparisons to current treatment standards. You can read more about reimbursement in Mark Curtis’ post on therapeutic headroom for cell therapies. Following pCODR approval, the provincial Ministry of Health determines how the drug will be funded in the province. Lack of pCODR approval doesn’t necessarily mean that the drug isn’t accessible to patients; it simply means that patients will be required to pay out-of-pocket (or with insurance), ironically making the drug inaccessible to some patients.
You can already see that between clinical trials and drug approval, it’s no wonder that it takes a long time for cancer drugs to become available in Canada (or anywhere for that matter). However, cancer drugs face an additional limitation during their clinical trials: the study participant population. Due to the undetermined risks and effectiveness of the new drug, participants in Phase I and II cancer drug trials must have either (a) failed the current standard of therapy, or (b) have no other treatment options.
While this does a great job in ensuring that patients receive the best, known treatment, it means that new cancer drugs are facing an uphill battle: they begin their testing in the sickest, most advanced cancer patients. This means that unless the new drug is extremely powerful, it may be found to not have the desired effects, and fail the clinical trial, simply because the disease in these patients was too advanced. This seems unfair, but these advanced patients are the ones who actually need the new drug – other patients were successfully treated with other therapies. If a drug doesn’t work in these patients, nothing has been lost (but nothing has been gained either). And as I am ever the optimist, I like to think that if a drug works well in the sickest of patients, it has the potential to work even better in less advanced patients.
I may not have reassured you with this post, but hopefully you at least understand why the process takes so long. In the meantime, if you’re wondering about ongoing clinical trials for cancer drugs in Canada (of which there are 715 actively recruiting!), check out Canadian Cancer Trials.