JR is a 43-year-old man with a primary hepatocellular carcinoma. He was diagnosed 6 months ago with metastatic disease and today has been told that there are no remaining conventional treatment options available for the management of his cancer. To look at this patient is to see a young man who seems to be otherwise healthy, a man who continues to work full time, to travel, and to be an active husband and father. Only his distinct yellow skin coloration betrays him and reveals to all who see JR that his liver is failing and, in the absence of some treatment that can slow his disease, will result in his demise in the weeks to come. JR’s menu of options is more limited than ever. He can choose to accept the finality of hospice care or take a chance on an unproven investigational therapy in the setting of a clinical trial.
This is a scenario that is repeated every day in oncology practices around the world. As a clinical oncology pharmacist in a community practice setting, I am intimately involved in the treatment planning and decision-making process for our patients and am routinely called upon to evaluate clinical trial options for patients like JR. For some patients, the hope of a miracle cure becomes the driving force behind their desire to receive an investigational drug. For others, it is their sense of benevolence, their recognition that while they may not receive much benefit, they may be helping future patients with the same type of cancer. The strict inclusion and exclusion criteria for late-phase clinical trials often exclude patients with end-stage disease due to their organ failure or short life expectancy. However, phase 1 trials of the most unproven novel agents will sometimes (but not always) welcome these patients. For healthier patients, a later-phase clinical trial may be an appropriate option that allows them the potential to live longer.
One of our duties as oncology practitioners is to scrutinize every available option in order to ensure to the best of our ability that these novel agents and their corresponding studies are reasonable and safe for patients. This is not always an easy task, especially when patients are referred to a site in another town or state. The concerns of both patients and practitioners may cause hesitation as we ask what standards are in place to ensure that the maxim “do no harm” will apply to these already fragile patients, as they are thrust into a world of a new oncologist, a new large academic medical center, and an unapproved treatment option.
Fortunately, many of the assurances related to novel drug agents and their evaluation in clinical trials come via the US Food and Drug Administration (FDA)’s investigational new drug (IND) process and current good manufacturing practice (cGMP), as outlined in the Code of Federal Regulations (CFR) Title 21. This highly regulated procedure ensures that prior to beginning studies, the manufacturer or sponsor must submit an IND application that includes chemistry, manufacturing, and control information, which the FDA reviews to determine whether or not the new drug possesses the properties and reasonable safety to permit treatment of human subjects. Unlike the case of drugs that are ready to enter phase 2 or 3 trials, it is recognized that phase 1 agents may be manufactured on a small scale, and thus are not held to the same high standards. As such, cGMP rules for phase 1 drugs relate mainly to the manufacturer’s written procedures, policies, and protocols; appropriately controlled and maintained equipment; the manufacturing environment; and assurance of data quality recorded and reported by the manufacturer.1 In addition to these fundamental elements of safety, drugs produced in larger quantities in traditional manufacturing facilities for the express purpose of use in later-phase clinical trials must adhere to more stringent provisions for drug processing, packaging, and labeling, as also outlined in CFR Title 21. While there exists variance in the rules for the manufacturing of drugs at various stages of development, a common theme is ensuring patient safety beyond the inherent risks of drug toxicity and uncertain efficacy associated with any medication.
Are cGMP regulations sufficient? As oncology providers, it is our duty to question the likely value of each and every drug and combination regimen that we prescribe for our patients. While we are trained to adhere to clinical practice guidelines and make evidence-based decisions, at times it is the art of medicine and the associated gut instinct that allows us to personalize therapy when a clear and concise course of action is uncertain. Whether we elect to pursue a clinical trial with a novel agent or an unconventional combination of commercially available drugs, there is some comfort in knowing that cGMP rules exist to ensure that the drugs our patients receive are unadulterated, contain the expected active ingredients and excipients, and have been prepared in a properly maintained facility.
Because I am a pharmacist involved in conducting all phases of clinical trials, it is often my responsibility to educate patients on a study’s design and, most importantly, the investigational drug itself. Frequently I am asked,Would you recommend this drug (or this study) for a family member? While I can read the medical literature, seek to understand the mechanism of action and likely toxicities of a novel agent, and share with patients results from earlier studies, I cannot personally attest to the composition of the drug product that they take orally or receive intravenously. It is precisely for this reason that I am thankful that a regulated process exists precisely for this purpose. Even still, mistakes occur and unsafe medications cause harm by reaching patients every year. A review of the FDA’s database of warning letters reveals that even with the best of intents, these regulations are violated from time to time. Fortunately, the number of identified cGMP issues is small, and when issues are identified, the FDA has the authority to shut down the production facility and recall adulterated medications. The consequences for endangering the public by violating these rules are often severe, which should also provide some confidence in the safety of the drugs that we prescribe. Overall, the system works more times than not, and I feel confident in the quality of the drugs that my patients receive either from commercial sources or as part of a clinical trial.
In conclusion, it is important to recognize that the benefits of cGMP are not standardized around the world. Drugs produced in other countries may not be as highly regulated, resulting in inconsistent drug contents, among other issues. As pharmacists, we are often referred to as the drug therapy experts, and as such, I think it is safe to say I speak for my peers by suggesting that these are some of the many reasons why the general public should seek to avoid drugs that are produced in locales where high standards are the exception rather than the rule and the safety of drug products cannot be ensured. In the United States, cGMP at a minimum provides some assurance that the drug production process is safe, well maintained, and regulated at a high level.
- Guidance for Industry. cGMP for Phase 1 Clinical Trials. July 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070273.pdf. Accessed September 2, 2014.