Life in a Clinical Trial: The Bird's Eye View

With the first few months of my clinical trial behind me and the initial scans showing positive news, I'm now in a position to offer meaningful information and perspectives about the trial in which I'm taking part. I also think it might be useful to explain a little bit about the clinical trial process, because a number of loved ones have admitted that they're somewhat confused about what exactly taking part in a trial means. So, let's dive right in! 

In order for a prescription medication to be approved for use in the United States, it must undergo rigorous testing and be approved by the US Food and Drug Administration (FDA).  There have been debates recently about whether the FDA's approval process for prescription drugs is too arduous and time-consuming - but personally, I support the extensive data collection and testing process. When you're offered a drug that could be the difference between life and death, you sorta want to know that said drug has been put through its paces and is safe for use! Because of its processes and policies, the FDA is a clear leader in protecting public health around the world and in keeping Americans safe from poorly designed or potentially dangerous medicines that originate in other nations. Many other countries have modeled their own government organizations for bringing drugs to market after the FDA. (The FDA also approves medical devices, food items, and so on, but that's for someone else to discuss. I'm not a scientist, after all!)

According to the California Biomedical Research Organization, it takes about 12 years for a drug to make the journey from the lab to your medicine cabinet - and drug development is a very costly undertaking; on average, a single drug costs a little over $350 million to develop! You can see why prescription drugs are often so expensive...especially when you look at the statistics of how many drugs even make it to market: only about 5 out of every 5,000 drugs even make it to the human testing phase, and then only about one of these five winds up on the market. Crazy, right? (Now you can start to see why cancer fighting drugs are so expensive. Biotech companies need to recoup their losses for all of the drugs that didn't make it to market as well as the costs incurred bringing the successful drug to market. If they're publicly traded companies, they want to make a profit as well. So there you go: research and development costs are rolled into prescription drug costs.)

Why is it so expensive to develop a drug? Part of the answer is that it has to go through a number of different rigorous and necessary testing phases. First, the scientist gets an idea, and she and her teams begin to work out those ideas in the lab. Once the idea has made it through the lab and looks as if it really could become a viable drug, it then goes through trials with various animals. All of this costs money and time and resources. Finally, it's time to test things out on the humans. Human trials are broken into three phases: I, II, and III. 

• Phase I trials involve a very small number of people and exist to discover side effects and find manageable dosing schedules and levels, so the trial director may increase doses of the drug over time or fiddle with the dosing schedule (is every two weeks efficient? How about every week? Every day?) to see whether and how such adjustments affects patients' quality of life and response to the drug in question. These trials are usually very small, sometimes including only a few dozen patients. Usually, people participating in phase 1 trials have run out of existing treatment options for their disease. (I feel compelled to add that this is not the case for me - these new immunotherapies are very promising and my disease was pretty stable when we decided to give it a try. Stability mattered because immunotherapies generally take longer to start working than chemotherapies, so the "standard" Phase 1 patient, the one who has run out of options, might not have time to wait for the immunotherapies to start working.) Phase one trials exist over various periods of time. My trial says that I personally will be "under study" for 29 weeks, but that the entire phase one will be complete and reported on in about three years. (It also says that I can continue to take the drugs past the end of the active study period as long as they continue to work for me; conversely, I have the right to leave the study if it happens that I stop responding to the drugs.)  
• Phase II trials are designed to illustrate that the drug under study is at least as efficacious and safe as existing treatments. Of course, the developer hopes the drug will provide even better results than existing treatments and be just as safe. This phase will place some people on standard treatment and others on the trial drug, or may use a placebo, and so on, in order to make their case.  Patients will not know what group they are in (this is called a randomized trial). The number of participants is larger, but still very small, usually topping out around a couple of hundred participants. This phase usually takes a couple of years.
• Phase III trials are the last hurdle before a drug is approved and allowed on the market. The study directors will now recruit large numbers of people - sometimes thousands of people - and be sure to include different ages, genders, ethnicities, and so on to see if the drug continues to replicate the results found in the first two phases. This, too, will be a randomized trial. They will be looking closely at side effects, efficacy, and, especially, at whether the new drug offers better outcomes than the standard drugs in use. These trials can sometimes take a number of years to finish.
• Note: With immunotherapies seeing such significant successes in some cancers and patient populations, there have been some instances lately where a Phase (usually Phase II) is skipped in order to finish testing and get the drug to market so that more patients can use it. There have also been incidents in which the randomized trials were cancelled after a certain point, and everyone participating in that phase begins receiving the drug in development. 

So. I am participating in a Phase I human trial. As I mentioned above, this is not because I am out of treatment options. I'm happy to be in a Phase I trial right now because in Phase I, everyone is guaranteed to receive the trial drug.  Once I signed a whole bunch of paperwork and joined the trial, I agreed to stop receiving the standard treatments I had been receiving up to that point. So I discontinued use of Xeloda (chemo drug; also used with metastatic breast cancer patients; it's taken orally at home rather than at the hospital as an infusion) and Avastin (a monoclonal antibody drug that cuts off blood supplies to tumors; this one is an infusion), both of which had been serving me quite well for 21 months. In order to start the trial, I had to be free from any cancer fighting drugs for 6 weeks. That was an anxious time. But as explained in earlier posts, I made it through that and after all the spleen shenanigans, I began receiving treatment in early March. 

The only cancer fighting therapies I receive while I am in the study are the study drugs. A number of my friends and relatives have been confused about this, wanting to know when I'm getting chemo and when I'm doing stuff for the trial. It's a full time thing.  Once you're in a trial, you're "under study" and you take the study drugs (along with whatever other meds you might need that aren't cancer fighting drugs. I take Effexor, for example, and I also am required to take a blood thinner, Fragmin. These both pre-date the trial and I didn't stop taking either of them) and that's it. You also have to undergo regular tests and scans - the tests (for my study, anyway) gauge how the medication is affecting your various systems, enzyme levels, and so on; they consist of regular bloodwork, but I also have my vitals taken every 15 minutes while I'm receiving infusions and for up to two hours after each infusion. Once a month, I have to have an EKG right before the infusion begins.  Then there are the scans. I undergo CT and MRI scans every 8 weeks; they tell us whether the medications are working by measuring my existing lesions to the nearest millimeter and seeing if they've grown, shrunk, or stayed the same. This study is on a schedule in which I receive one of the medications every two weeks (an infusion) and then the other medication every 4 weeks (also an infusion; so every other visit, I receive two infusions. The drugs cannot be administered at the same time, so that visit is a long day). 

A little more about the trial I am a part of: my study is looking at not just one, but two immunotherapy agents and how they work together. One of the drugs I'm taking, durvalumab, has already been approved for use - but for another type of cancer. This made me feel more confident about the trial, since it has already been studied thoroughly in people.  The other one doesn't even have a name yet - just a number, and when I signed my trial paperwork, I was informed that about 95 people have already taken this drug. I think the total number of people will be around 200 people by the time this phase is complete. So this study isn't just trying to get one drug to market - it's trying to get a specific combination to market.  If the trials are successful, the developer will market the drugs together as an immunotherapy treatment option for patients living with advanced colorectal cancer (CRC) and a few other cancers, too. The combination is important because so far, developers have had little success working with just one drug for the version of CRC that I live with (I'm MSS, which is what 95% of CRC patients are). Why? Well, my understanding is that unlike a number of other cancers, MSS colorectal cancers usually feature cancerous cells that don't have many mutations. Think of mutations as doors or windows - they make it easier for your immune system to break into the cancer cell and destroy it. In addition to this, CRC cells are able to hide themselves from your immune system (think Invisibility Cloak). So, the immune system doesn't even see the cancer cells hanging out right there nibbling up space, and even when the immune system recognizes a cancer cell as the enemy, it can't really get in there to burn the place down. So one of the therapies I'm taking is a PD-L1 inhibitor. In human terms, this means that it pulls the Invisibility Cloak off of the cancer cells so that they're visible to the immune system. And then, once the cell is all naked and embarrassed and has an angry mob of immune system groupies rushing around it trying to figure out how to blow it up, the second drug boosts the capabilities of both my NK cells (which stands for Natural Killer!) and T cells (which stands for tee-ball! I am just kidding! I have no idea what the T stands for!). Both of these cells are kinds of white blood cells and their jobs are to kill invaders in your body. So my NK and T cells basically get handed ginormous power loader suits like the one that Sigourney Weaver wore in Aliens to crush the aliens. And then they go to town, just pummeling those cancer cells until they fall apart and then, for good measure, they stomp on the pieces until there's nothing left of those little bastards. Voila!  *Ahem* Let me rest a moment - I've gotten a bit carried away and managed to make cancer sound like a sci-fi movie. But hey, whatever works to help you, Dear Reader, understand what's going on!   

So, that's a little primer on clinical trials and my specific trial. Up next: how my body has reacted to the study drugs! Fun stuff!