When the Phases are Exhausted

Clinical Researcher—March 2021 (Volume 35, Issue 2)


Preethi Sriram, DHSc, MSN, BSN


The approval process for new drugs in the United States is designed to be rigorous, and the U.S. Food and Drug Administration (FDA) provides oversite and monitoring of the overall process through regulations and guidelines in order to ensure that new products are both safe and effective once made available to the general public. In order to accomplish this, the FDA requires those developing new drug products to conduct safety and efficacy studies in an exact manner.{1}

After preclinical studies are conducted, the different phases of clinical trials in human subjects are Phase I, II, and III before any approval and marketing of a new drug product, followed by the possibility of Phase IV postmarketing studies.

Portney and Watkins{2} describe the preclinical phase as happening in laboratory settings, often in animal models, before a drug is tested in humans. Phase I is described as when researchers start experimentations in humans to collect data on the dosage, timing, and side effects of the drug, and is usually conducted on a sample set of subjects that range from 20 to 80 participants who may be healthy or, as is often the case for oncology drugs, may have the indication of interest. Phase II comes next in a larger set of participants who are always patients if the therapy has been shown to be safe in Phase I, and this is when the drug is studied to demonstrate its efficacy. Phase III studies are randomized, double-blinded experiments that compare the new drug with the standard of care or placebo, and these trials usually involve the largest subject populations, ranging from hundreds to even thousands of participants. Phase IV studies are described as taking place after the drug has been approved, when the researchers may continue to investigate its effects in cases of other therapeutic indications or in different populations than those involved in the original trials.

Considering the Options

When a patient with a difficult-to-treat condition is not enrolled in a clinical trial due to not meeting the criteria of the study, or when there is no trial available for his or her specific disease, it may seem that there are few options left regarding cutting-edge treatment. The remainder of this article discusses lesser-known avenues to enrollment in clinical trials, the possibilities for using repurposed drugs that are already on the market for some other condition in off-label circumstances, and details of how compassionate use or expanded access studies are managed.

Access to Clinical Trials

In situations of rare diseases/terminal illnesses, it is important to know what treatment options are available for individuals apart from current standard of care, including the options within clinical trials.

Unger et al.{3} notes there are four barriers with regard to clinical trials—structural, clinical, physician, and patient barriers—expanded upon here with more detail:

  • Structural barriers occur when a patient who would otherwise be willing to participate in a clinical trial finds that none are available for his or her condition at a particular treating institution.
  • If a trial is available and the patient is assessed for eligibility but excluded due to not meeting the inclusion criteria, this is a clinical barrier.
  • A physician barrier occurs if the patient would be eligible for a study but his or her physician never mentions the study, essentially taking the choice away from them.
  • Patient barriers may include factors related to treatment preferences, transportation- and work-related challenges, income and insurance levels, family and peer pressures, religious beliefs, and other considerations.

A study by Carey et al.{4} found that the major barrier to trial participation is that potential participants are not invited to be screened for studies. Meanwhile, Duma et al.{5} conducted a review on cancer clinical trials conducted from 2003 to 2016 and found that, from the 1,012 trials reviewed, only 310 (31%) documented the ethnicities of the 55,689 total participants in those studies. It was noted by the authors that, when ethnicities were recorded, participation varied by ethnic groups and that non-Hispanic whites were more likely to be enrolled than African Americans and Hispanics. Another finding from the review was that subjects younger than 65 years of age had a higher likelihood of being enrolled than the elderly. Low recruitment was also noted amongst females compared to males. The authors note that most of the trials included in the analysis were completed between 2013 and 2017, and that the ratio of participation of minorities decreased following 2011.

It is important for both patients and providers to be aware of how to find clinical trials. One online resource on this topic{6} notes that a starting place is the website www.clinicatrials.gov, a registry of trials maintained by the United States National Library of Medicine at the National Institutes of Health (NIH) and holding registrations from more than 329,000 trials from 209 countries. Another resource{7} providing information for where to search for cancer indications notes that the National Cancer Institute’s Cancer Information Service can provide a tailored search for clinical trials, and that many of the advocacy groups that exist for specific types of cancer maintain lists of relevant clinical trials or can refer individuals to organizations or websites that match patients to trials.

A resource for patients with rare diseases{8} notes that disease advocacy organizations have medical boards and services for physician locators and/or networks for patients, all of which can help in finding healthcare professionals who are familiar with specific conditions. Further, the Genetic and Rare Diseases Information Center helps patients find advocacy groups related to their specific conditions, and the Patient Recruitment and Public Liaison Office at the NIH provides information about participating in research at NIH hospitals.

It is important for healthcare providers to be aware of such resources as these as they seek to help patients find trials for which they may be eligible. Table 1 summarizes various resources that both providers and patients can utilize.

Table 1: Resources for Patient and Providers Who Are in Search of Trials

Source Website/Contact Summary
ClinicalTrials.gov https://www.clinicaltrials.gov/ A database of privately and publicly funded studies conducted around the world.
National Cancer Institute (NCI) Cancer Information Service https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cancer-information-service

1-800-4-CANCER (1-800-422-6237)

This is NCI’s link to the public for interpreting and explaining research findings in a clear and understandable manner, and for providing personalized responses to specific questions about cancer.
National Organization for Rare Disorders (NORD) https://rarediseases.org/for-patients-and-families/connect-others/find-patient-organization/ Lists free resources for patients and families affected by rare diseases. Organizations interested in being listed should contact membership@rarediseases.org.
RareConnect https://www.rareconnect.org/en/communities RareConnect responds to rare disease patients’ need for information and connection by creating international online communities and discussion groups for specific diseases.

For Physicians: How to Request Single Patient Expanded Access (Compassionate Use)



When a physician wants to submit a Single Patient Expanded Access request to obtain an unapproved investigational drug for an individual patient, he or she must first ensure that the manufacturer is willing to provide the investigational drug for expanded access use. If the manufacturer agrees to provide the drug, the physician should follow the steps given to submit an Investigational New Drug application to the FDA.
Genetic and Rare Diseases (GARD) Information Center https://rarediseases.info.nih.gov/diseases  

GARD maintains a list of rare diseases and related terms to help people find reliable information.


National Institutes of Health (NIH) Patient Recruitment and Public Liaison Office https://clinicalcenter.nih.gov/participate1.html


Professional nurses answer questions and provide information regarding the NIH Clinical Center’s clinical trials and associated topics. Both the general public and practicing physicians may ask for details on specific research studies and the criteria for patient referral.
Expanded Access for Medical Devices


https://www.fda.gov/medical-devices/investigational-device-exemption-ide/expanded-access-medical-devices This page is intended to help healthcare providers and device manufacturers learn about expanded access options for medical devices and associated criteria and requirements for each.


 Repurposing of Drugs for Off-Label Use in Clinical Settings

Fajgenbaum and Rader{9} note that repurposing drugs is faster and far more economical than starting development of a new drug from inception, as many targets for drugs are shared across different diseases. The authors also note that historically, there have been many notable success cases for drug repurposing, for instance sirolimus for lymphangiolyomyomatosis.

In another publication, Fajgenbaum et al.{10} note that the COVID-19 pandemic is the largest pandemic that has been seen in decades, yet in its early days there were no specific, FDA-approved drugs for use in COVID-19 patients. The authors provide a systematic review of numerous off-label treatments for possible use against COVID-19.

Further, in his book, Chasing My Cure: A Doctor’s Race to Turn Hope Into Action,{11} Fajgenbaum describes how an uncle of his was diagnosed with metastatic angiosarcoma. When asked if a sample of the tumor could undergo genetic testing, the healthcare provider declined, saying that such testing, in the opinion of the doctor, would only impact treatment selection in 10% of the population. The author delved deeper and requested that a PDL-1 test be performed, and if the test was positive, that the doctor consider treating his uncle with an FDA-approved PD-L1 inhibitor or its receptor. The provider’s response was that, even if the test was positive, the drug most likely would not work and would be expensive. In the uncle’s course of getting a second opinion, an oncologist performed a genetic test that found the cancer cells were positive for PD-L1. The author’s uncle was prescribed one of two already FDA-approved drugs for lung cancer and melanoma. After starting the drug, the uncle showed dramatic improvement in his symptoms, laboratory abnormalities, and tumors. Faigenbaum notes the particular case of his uncle receiving the drug has led to other off-label use of it, as well as to new clinical trials for the drug and drugs similar to it.

In many life-or-death situations, patient advocacy can benefit patients who do not have medical or healthcare backgrounds by helping them to conduct self-study on their therapeutic indications. It can also help them to seek guidance from trusted healthcare workers, or someone who is knowledgeable about their disease state, who can advocate for them regarding off-label use of a drug that is already on the market.

Compassionate Use/Expanded Access

In a memoir, The Perfect Predator: A Scientist’s Race to Save Her Husband from a Deadly Superbug,{12} an American husband-wife couple writes about how the husband had become sick when vacationing in Egypt and was taken to a local hospital for potential treatment. From there, he was flown to a hospital in Germany, where a psuedocyst was discovered growing on his pancreas which had a bacterial strain of A. baumanni that is resistant to antibiotic treatment. He was flown back to America for further treatment and care, and his wife learned from her research on the condition that certain viruses known as phages could be of use in such conditions. In an interview conducted by Corbyn,{13} the authors describe how phages were first discovered in 1917 by Felix d’Herelle, but he unfortunately had an arduous time getting the work accepted because he lacked formal medical training and was considered a “vagabond scholar.”

The authors also describe in the interview with Corbyn that, after penicillin came to the market in the 1940s, phage therapy largely fell out of sight in the West during the Cold War but continued in Russia. While conducting this research, the wife, who is a colleague and friend of the chief of infectious diseases at UCSD School of Medicine, shared her findings with him, and he agreed that if she were able to find phages that matched the bacterial infection for her husband, he would contact the FDA and get approval for compassionate use of the experimental therapy. With help from a researcher from Texas A&M University, a phage was found that could be used against A. baumanni. The wife was also able to access another phage cocktail from the U.S. Navy, which was the treatment that ultimately worked in her husband’s case.

While this example is heartening and shows a successful pathway taken in an extreme situation, it is important to realize that not everyone may actually get the off-label drug required for their condition in the same manner. For example, Rangarajan{14} describes having a daughter with a lysosomal storage disorder and how her physician followed the protocol of the pharmaceutical firm Shire for applying for compassionate use of one of its products in her case. The drug was already being tested in clinical trials, but the daughter was not eligible for them, and the company denied the request. The author notes that while there is, in theory, a “right to try” policy allowing those who are critically ill to go directly to the company and bypass the FDA, there is nothing forcing the company to take positive action in any particular case.

For the case of the patient or family advocating for expanded use, it is important to work with experts in the field and doctors who are willing to help in seeking FDA approval for trials or help in managing a pharmaceutical company’s appeals process (see Table 1).

Devices vs. Investigational New Drugs

While the examples referenced so far have related to clinical trials of drugs and their off-label uses, similar concepts can be applied with regard to medical devices. Information from the FDA.gov website{15} notes that expanded access is a potential option for patients with serious or life-threatening indications to gain access to medical devices that have not been approved for treatment outside research studies—assuming there are no comparable or reliable alternative therapy options available. The three options noted by the FDA outside clinical trials include emergency use, compassionate use, and treatment Investigational Device Exemption (IDE). It is noted that, while emergency use of an investigational device does not require FDA approval, compassionate use and treatment IDE do; all three require follow-up reports as well to the FDA (see Table 1).

Seeking Second Opinions

Katella{16} notes that Yale Medicine doctors often see patients who would like to obtain second opinions on their conditions but worry about insulting their primary doctors. Noting that truly professional doctors are not offended by such desires and that second opinions may be important in some cases—for example, in complex disease situations or when the treatment plan is unclear—Katella adds that the process can include getting a referral from the current doctor and determining if insurance will cover the cost. Further it is important to gather documentation on the patient’s relevant medical history and the original doctor’s reports to be shared with any secondary healthcare providers being consulted.


Clinical trials should be accessible by all people, regardless of racial/ethnic background, age, or gender; however, we can see from literature this is not always the case, especially for those who are racial/ethnic minorities, elderly, and females. In cases when patients are faced with rare diseases/terminal illness, it is important that the healthcare provider help the patient and his or her family seek potential options for appropriate clinical trials. If the patient is not eligible for a trial, or in situations when there is no trial that is available, the patient and family could conduct research into the therapeutic indication and seek expert consultation for potentially using drugs that are already available on the market for off-label use.

Table 1 summarizes resources that can be utilized in searching for trials and seeking further guidance for individual patients and their healthcare providers. In certain scenarios, the patient can also look into potential options for trying to enroll in compassionate use studies of experimental drugs or devices through FDA approval or allowance by the company testing the product.

There are benefits and limitations to each of the options described in this article, and it is important for the patient and family to work alongside their healthcare provider in order to determine the next best steps for patient treatment and care.


  1. Liu M, Davis K. 2010. A Clinical Trials Manual from the Duke Clinical Research Institute: Lessons from a Horse Named Jim. Wiley, USA.
  2. Portney LG, Watkins MP. 2015. Foundations of Clinical Research: Applications to Practice(Vol. 3rd). Philadelphia, Pa: F.A. Davis Company.
  3. Unger JM, Vaidya R, Hershman DL, Minasian LM, Fleury ME. 2019. Systematic Review and Meta-Analysis of the Magnitude of Structural, Clinical, and Physician and Patient Barriers to Cancer Clinical Trial Participation. J Natl Cancer Inst 111(3):245–55. doi:1093/jnci/djy221
  4. Carey M, Boyes AW, Smits R, Bryant J, Waller A, Olver I. 2017. Access to Clinical Trials Among Oncology Patients: Results of a Cross Sectional Survey. BMC Cancer17(1):653. https://doi.org/10.1186/s12885-017-3644-3
  5. Duma N, Vera Aguilera J, Paludo J, et al. 2018. Representation of Minorities and Women in Oncology Clinical Trials: Review of the Past 14 years. J Oncol Pract 14:e1-e10.
  6. How to Find a Clinical Trial. https://www.webmd.com/a-to-z-guides/how-to-find-a-clinical-trial#
  7. Steps to Find a Clinical Trial. https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/trial-guide
  8. How to Find a Disease Specialist. https://rarediseases.info.nih.gov/guides/pages/25/how-to-find-a-disease-specialist
  9. Fajgenbaum DC, Rader DJ. 2020. Teaching Old Drugs New Tricks: Statins for COVID-19? Cell Metabolism32(2):145–7. https://doi.org/10.1016/j.cmet.2020.07.006
  10. Fajgenbaum DC, Khor JS, Gorzewski A, Tamakloe MA, Powers V, Kakkis JJ, Repasky M, Taylor A, Beschloss A, Hernandez-Miyares L, Go B, Nimgaonkar V, McCarthy MS, Kim CJ, Pai RL, Frankl S, Angelides P, Jiang J, Rasheed R, Napier E, … Pierson SK. 2020. Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review. Infectious Diseases and Therapy 9(3):435–49. https://doi.org/10.1007/s40121-020-00303-8
  11. Fajgenbaum D. 2020. Chasing My Cure: A Doctor’s Race to Turn Hope Into Action (pp. 228–9). New York: Ballantine.
  12. Strathdee S, Patterson T. 2019. The Perfect Predator: A Scientist’s Race to Save Her Husband from a Deadly Superbug. New York, N.Y.: Hachette Books.
  13. Corbyn Z. 2019. Steffanie Strathdee: ‘Phages Have Evolved to Become Perfect Predators of Bacteria.’ https://www.theguardian.com/science/2019/jun/15/steffanie-strathdee-phage-therapy-interview-perfect-predator
  14. Rangarajan V. 2018. The ‘Cruel Joke’ of Compassionate Use and Right to Try: Pharma Companies Don’t Have to Comply. https://www.statnews.com/2018/06/05/right-to-try-compassionate-use-pharma-compliance/
  15. Expanded Access for Medical Devices. https://www.fda.gov/medical-devices/investigational-device-exemption-ide/expanded-access-medical-devices
  16. Katella K. 2020. Can a Second Opinion Make a Difference? https://www.yalemedicine.org/news/second-opinions

Preethi Sriram, DHSc, MSN, BSN, (SriramPreethi@hotmail.com) is a Clinical Research Professional in Raleigh, N.C.