A Rational Approach to Finding the Best Clinical Trial

Disparaging times require innovative thinking. I am the son of a mother who died from cancer on June 27^th, 2009. I share my research, learnings, and perspective in her honor. I also happen to be a director in a biotech company who has spent a great deal of time interfacing with researchers, doctors, and other health care professionals. I consider myself a detailed thinker who often analyzes and sometimes challenges conventional approaches. I have used much of what I have learned over the years in the pharmaceutical/biotech environment, coupled with my relentless research in the area of clinical trials and novel healthcare delivery to improve my mother's odds of survival and increase her own mortality for as long as was possible.

During my mother's three year battle with synovial sarcoma, I have learned much more than I had previously known about clinical trials. I have also reconfirmed my belief that physicians’ really do have only the best interest of their patients in heart as they make medical recommendations. I am not a believer in homeopathic medicine (except as an adjunct to therapy) when there are proven conventional therapies available to which have been extensively studied. I am clinically minded and believe in a rational approach to treatment. In my mother’s case, I had preferred she explore experiential medical trials once conventional therapies failed before trying certain homeopathic therapies that many of her friends had suggested. Why? Even unproven and unstudied new bio-engineered therapies must meet vigorous “proof of concept” controls before human research may begin. A drug’s mechanism of action must be compelling enough to suggest that it MAY work in humans. Exhaustive pre-clinical research must be first demonstrated by in-vitro studies (laboratory experiments) and in animals before a phase I trial can be conducted in the United States. Additionally, most preclinical animal studies are conducted in only those animals that have a disease condition, mutation, or structure that is most similar to the disease occurring in the human condition. (The ability to predict human success based on animal studies is very weak. The costs are so exorbitant around moving a drug from preclinical to human trials that researchers attempt to do everything they can to predict those compounds most likely to succeed. One way they do this is to give thought to the animal that is studied. Many animal studies involve "knock out" genes. Researchers must find an animal with the similar gene to the one in humans that is believed to trigger the tumor/disease. Thus, the previous company that I worked for had focused on developing treatments for retina diseases. Rats were not suitable to study as they lacked a gene thought to be associated with Macular Degeneration. Rabbits, however, did have this gene and were subsequently selected at much greater costs to the company.) As you can see, even animal research is carefully planned and scrutinized. Therapies in early stages of clinical trials have some degree of science and research to support their usage. Two other considerations I had for my mother was that (1) certain homeopathic therapies may disqualify her from medical trials. It is paramount that patients speak with their physician before trying even the most benign homeopathic remedies. (2) When conventional therapy (i.e. chemotherapy) has failed, a great deal of thought should be given before retreating with another version of the first therapy. In my mom’s case, her physician recommended another type of chemotherapy but confided that he did not have much hope in this regiment for her disease. It was necessary to remind her physician multiple regiments of chemotherapy are one of the biggest excluders from patients entering an experimental cancer trial. Many trial designs state that patients should have failed on only one regiment of chemotherapy in order to be deemed eligible for inclusion.

I recognize that the road to success is paved with good intentions. There are literally thousands of clinical trials that occur in this nation every day. In fact, hundreds of trials may be designed to address your specific condition. For patients with terminal and/or degenerative diseases, the luxury of time to enroll in multiple clinical trials is not always possible. My experiences in the biotechnology industry along with my understanding around clinical trials and physician education have revealed an inadequacy in most physicians’ ability to research and sometimes pick the best clinical trial for their patient. Let me first say that I am a big believer in putting your health and healing in your physician’s hands. I merely advocate that clinical trial selection for terminal patients is too important to not supplement your physicians’ clinical trial research with that of your own. Throughout this blog, I will share with you steps you may take to increase the odds of getting enrolled in the best clinical trial. This is even more of an important consideration when a patient’s lifespan is limited due to disease progression. If the natural history of your disease suggests a typical lifespan to be about one year, and most trials require at least a two month enrollment before a decision to continue or disqualify from treatment can be ascertained, then one must typically prepare for an opportunity to enroll in at most, five trials. Now consider that most trials require a thirty-day washout period (break) between finishing one and beginning another to ensure the earlier medication has completely left one’s body. This may mean that a terminal patient who follows the natural course of disease may have only four trial enrollment opportunities to find success.

Make no mistake that you as a patient can take actions to position yourself for a potentially better health outcome when it comes to clinical trials. You must also be realistic that the vast majority of patients will not significantly benefit from the drugs studied in early clinical trials. I am happy to share my thoughts and welcome you to discuss and challenge them as you'd like. Those of you who read this with close attention may be in the same position that my mother was in 2009 and as such, it is too important to not better understand, and yes- sometimes even challenge the decisions of your physician around their decision for trial selection.

First let me say that I am so very sorry that the severity of your medical diagnosis has led you to this blog. Based on the life threatening nature of your condition, there is no doubt that you would first want to search for the best physician, the best hospital, and the best treatment for your disease. Research has shown that the best predictors of success around hospital and physician selection are volume. Simply put, you can improve your odds of success by selecting a doctor or hospital that routinely performs your specific procedure/treatment often. Thus, a suburban hospital is rarely a better choice than a major academic center specializing in your disease.

Unfortunately, when it comes to treating these conditions, the ability to heal is ultimately out of the physician’s power after conventional therapy fails and as such, trials with experimental therapies are often looked to. This is yet another reason to seek out a "specialized" hospital / center of excellence for the disease that you suffer from. Pharmaceutical and biotechnology manufacturers often identify top academic hospitals to conduct their trials in as their reputation provides greater credibility to the promise of their drug to shareholders and investors within the company. Thus, Sloan Kettering Cancer Hospital will typically have better doctors and more promising clinical trials than North Harford County Hospital. Key take away: Pick a top hospital to undergo your treatment!

My mom lived in Baltimore, Maryland and came to realize a great sarcoma support network around the country. It helped her immensely to speak with patients going through the same challenges and undergoing the same experimental trials that she was. My mom was ready to begin a new clinical trial at Johns Hopkins hospital in Baltimore, Maryland and had the opportunity to speak with a patient who lives outside of San Francisco who was also on the same trial. She told my mom that her trial site was at UCLA medical center. She would fly down to Los Angeles one day a week for her infusion. If she was tired, she would check into a nearby hotel for the day and fly home in the evening. This reminded me how fortunate my mother was to live near a top hospital. A week later, I drove up from San Diego to a community center outside of Santa Monica, CA to attend a community lecture by an Oncologist. One of the questions posed to this physician was how likely he would be to send his patient to Europe for a novel clinical trial that is not available in the US. The physician answered by stating that this really didn’t happen. The medical communication sharing around the world is excellent and save for the exception that happened with one study in the 1980’s, a promising drug trial in Europe would be available in the US as well. He suggested that a patient may need to travel to MD Anderson Cancer Center in Houston, Texas or the Mayo Clinic in Rochester, Minnesota but assured the patient that there are closer options. This is when it occurred to me that the first way to vastly improve your odds of being assigned to a better clinical trial is to move to a location in the US that is close to several top academic centers. As mentioned previously, there are numerous clinical trials going on around the nation at one time. Drug companies seek out centers of excellence to conduct these studies. If one hospital is at capacity for running trials, a company will search for another. Thus, living in San Francisco, CA affords patients some good options for cancer trials but I would submit that the Northeast provides better from an ease of commute perspective. My mom was in the fortunate position to have multiple trials available to her at various hospitals without the undue cost of flights and hotels. Living in Baltimore, MD, she was in driving distance to the following hospitals: Sloan Kettering in NJ & NY (ranked # 2 in the US), Johns Hopkins in MD (ranked # 3 in the US), Dana-Farber Cancer Institute, MA (ranked # 5 in the US), Massachusetts General Hospital, MA (ranked # 7 in the US) along with other well recognized trial sites including National Institute of Health in DC, Hospital of the University of Pennsylvania (ranked # 14 in the US), and Fox Chase Cancer Center, PA (ranked # 20 in the US). There is no doubt that it is easier to apathetically accept enrollment in a hospital’s clinical trial that may be slightly less promising than another hospital’s trial if the transportation time and costs are too exorbitant. I was told by my parents to only make them aware of clinical trials in the Northeast area unless there was another trial in another hospital elsewhere in the nation that looked heads and toes better. Translation: We all want the best for my mother but a monthly airplane commute and hotel stay for an infusion at another trial site had better justify the expense. Especially since the probability of success for any experimental trial is quite low. Many folks may get upset when they devote a great amount of time to drive and wait at a renown medical center only to be seen by a medical resident or fellow. This is understandable but also recognize the trade offs. These medical centers typically have the most experimental trials offered since they have the staff (inc. fellows and medical students) to help run/manage the trials.

When you have identified your treating physician, I recommend that you inform him/her that you may like to reach out to another physician or two at times. A good physician should understand and feel confident by your desire to contact other physicians for second opinions and varying perspectives. In most sub-specialties, physicians are trained with different and sometimes opposing viewpoints. In Oncology, there are ‘Medical Oncologists’ and ‘Surgical Oncologists’. It may come as no surprise to hear that most Medical Oncologists prefer treating disease at the molecular level usually with pharmacological therapy. Surgical oncologists often embrace surgical intervention to halt the disease. I submit that it would be wise to communicate with multiple physicians when possible.

Most specialists stay up-to-date by attending the major conferences where studies and trials are reported on. The largest meeting that clinical oncologists attend is called the American Society of Clinical Oncology (ASCO) annual meeting. This meeting takes place in the beginning of June every year. There are about 25 different “tracks” at this meeting which enables physicians to attend lectures and gain information within an area (track) of their clinical focus. For example, physicians may choose to attend any of the following tracks at ASCO: Breast Cancer, General Oncology, Skin Cancer, Head and Neck Cancer, Sarcoma, Lung Cancer, Gastrointestinal Cancer, General Oncology, etc. By querying your doctor as to what track (itinerary) they have attended or plan to attend at the ASCO meeting may give you some insight into their level of focus and passion for your specific disease.

One of the biggest issues that get in the way of physician’s ability to provide uncompromising excellence is time. Recognize that practitioners advocate in the best interest of patients but they are human too. As a physician describes their work day, week, and month, one appreciates how little time they have to devote to the painstaking research necessary in determining whether one clinical trial offers even the most marginal benefit over another. Most physicians hear of promising clinical trials at the various physician meetings they attend on average of every four to six months. Oncologists have said that they learn of trials at www.clinicaltrials.gov but admittedly have very little time to scour this site. (At last check, there were nearly 90,000 active trials on his site.) The reality is that physicians will most likely recommend a clinical trial that is being conducted at their site/hospital. This is sensible from their perspective since they are more intimate and familiar with those trials. This is wonderful news for the hospital that derives a great deal of revenue from clinical trial enrollment, and the doctor who becomes closer to completing their enrollment goals necessary to speak and publish on the outcomes. It is also wonderful news for you as long as another location within the vicinity doesn’t have a more promising trial with active enrollment ongoing. Be your own best advocate and help your doctor!

The following detailed research will enable you to keep your doctor informed:

1. Visit www.clinicaltrials.gov

o All FDA approved phase I-IV trials are listed here and this is a source used by most physicians. (Just not to the degree that I will outline here.)

2. Select “Search for Clinical Trials” and input your SPECIFIC cancer diagnosis in the search box and hit enter. (i.e., search for “Synovial Sarcoma”… not just “Soft Tissue Cancer” even though Synovial Sarcoma is a form of soft tissue cancer.) There are some drugs that have demonstrated greater affinity for target tumors in certain diseases than others. If your specific disease diagnosis comes up in the trial search, it may mean (but not always) that the study sponsor (usually the manufacturer) believes their drug may specialize in your disease vs. a drug that is studied in patients with a general diagnosis of soft-tissue cancer. The flip side is that your condition may be so rare that it would take the sponsor too long to enroll patients without opening it up to a more generalized disease.

3. I prefer to select “Advanced Search” from this screen. Re-enter your specific diagnosis. Then change the following label values:

o Recruitment: Open studies

o Study Type: Interventional Studies (Disregard observational or diagnostic studies.

• Note: Expanded Access trials are certainly worth discussing with your physician. A challenge that exists with these trials is the extensive paperwork, effort, and time often necessary to begin receiving drug to initiate treatment. An advantage of these trials is that your physician often has greater latitude in administering the drug outside of the typical study protocols such as ensuring you receive active study medication, considering more factors in regard to the disqualification criteria, and they fact that this study may be done at your local location.

o Locations: I recommend leaving this blank during your first search and then tweaking it later to narrow down a very long list of trials if one exists.

o Gender & Age Group: Your gender and age.

o Phase: select phase II, III, and IV

• Phase I- These first studies in people evaluate how a new drug should be given (by mouth, injected into the blood, or injected into the muscle), how often, and what dose is safe. A phase I trial usually enrolls only a small number of patients.
• Phase II- A phase II trial continues to test the safety of the drug, and begins to evaluate how well the new drug works.
• Phase III- These studies test a new drug, a new combination of drugs, or a new surgical procedure in comparison to the current standard. A participant will usually be assigned to the control group or the study drug group at random. Phase III trials often enroll large numbers of people and may be conducted at many doctors’ offices, clinical, and hospitals nationwide.
  
  *Each drug typically takes a period of 10 to 15 years before it makes it to the market. Drug development includes about six-and-a-half years of discovery, preclinical testing, and toxicity studies; one-and-a-half years in Phase I trials to assess safety in healthy volunteers; then two years in Phase II trials with a few hundred patients to evaluate the drug's effectiveness and side effects. The development process continues with three-and-a-half years in Phase III trials involving thousands of patients and scores of research centers to confirm effectiveness and evaluate long-term effects, then one-and-a-half years of Food & Drug Administration review, where all the clinical trial data are presented. According to the FDA website, of 100 drugs for which investigational new drug applications are submitted to FDA, about 70 will successfully complete phase 1 trials and go on to phase 2; about 33 of the original 100 will complete phase 2 and go to phase 3; and 25 to 30 of the original 100 will clear phase 3 (and, on average, about 20 of the original 100 will ultimately be approved for marketing).
  
  

4. Review the title of each trial to determine what drug(s) are being studied. Determine those trials that are evaluating a newer drug therapy. Physicians are no doubt aware of those trials evaluating a generic/older drug. Additionally, these drugs can often be administered by your physician without the rigors of a clinical trial protocol.

• Note: Patients who are randomized to the control group of a trial involving a potentially lifesaving compound should recognize that there are compassionate provisions built into such trials. Most permit physicians/study coordinators to introduce “rescue medications” to patients randomized to control or placebo. Many trials are done in a ‘cross over’ design which enables the non-responding control group patients to ‘cross over’ to active treatment.

5. Open another tab on your computer (without closing the first one) and go to your web browser (Google). Enter the name of the drugs being investigated and run a search on each one. Perform a comprehensive review of all search results. This includes press releases, articles, abstracts, etc. Pay special attention to those studies and abstracts discussed on recognized sites like: ASCO, PubMed, MedLine, etc. (Note that you should also review the links on the second page of the search engine results as this is where you may find drug data reported in European and ex-US trials.) Print the most compelling information as this should be shown to your Oncologist.

6. Now determine the location for the trials. Note that you often must scroll down the trial page and expand the link entitled "trial sites". Determine your proximity to the closest trial site. Consider the frequency of visits necessary based on the study protocol. You should still research a drug that only may be studied outside your geographical vicinity as there may be a possibility for your physician to get the drug for you via the FDA's compassionate use policy. Also recognize that there are charities called 501(c)3 foundations of which manufactures may fund drug costs AND sometimes transportation/travel costs to study sites.

Co-Pay Assistance Options
Financial assistance may be available from independent charitable foundations for qualified patients who are unable to afford their out-of-pocket costs. Below is a list of foundations that may be able to provide financial support.
Healthwell Foundation
1-800-675-8416
www.healthwellfoundation.org
Patient Services, Inc
1-800-366-7741
www.uneedpsi.org
Patient Advocate Foundation
1-866-512-3861
www.copays.org
Patient Access Network Foundation
1-800-316-7263
www.patientaccessnetwork.org
National Organization for Rare Disorders (NORD)
1-800-999-6673
www.rarediseases.org
Chronic Disease Fund (CDF)
1-877-968-7233
www.cdfund.org
CancerCare
1-800-813-HOPE (4673)
www.cancercare.org
Leukemia & Lymphoma Society
1-877-557-2672
www.LLS.org/copay

*Compassionate Use - A physician can apply for special permission (under special circumstances) to obtain a non-approved drug for your treatment. This application must be granted by the FDA and the drug manufacturer. Although slightly time consuming, this drug may then be used per your physician's described protocol and not per the protocol mandated in the ongoing trials.

7. On a note pad, copy the names of the drugs/trials that have the bulk of promising data (per your simultaneous Google search in the other browser window) and list them in a ranking order from best (most promising) to the least. The following factors should be included as you subjectively rank the trials probability of success:
• the higher the phase of the trial, the higher odds of success and better likelihood of predictable and manageable side effects (i.e., Phase 3 have shown more promise to date that Phase 1 trials have.)
• If two trials look equally attractive, determine who the manufacturer is and research them! Why? There are many small pharma/biotech companies that attempt to develop a drug and either sell it to, or partner with, a major manufacturer when commercializing it. Smaller companies actively court the larger companies to invest in their company and their drug. Big manufacturers like J&J and Pfizer get solicited by literally hundreds of smaller companies touting the promise of their drugs every year! The dudiligence performed by the large companies cannot be overstated. These mega-companies have enormous means at their disposal to help them identify the most promising drugs to acquire or invest in. Their scores of statisticians, toxicologists, physician advisors, and epidemiologists evaluate the preclinical data for each opportunity presented to them. If a mega-company is involved with a drug candidate in a trial, you should consider that an enormous amount of dudiligence has been done before moving the compound to trial. The decision to move a drug to human clinical trials is very costly. As such, this action suggests their experts have a strong belief in the drug.
• You should also go to the web site of the company/manufacturer. If they are a publically traded company, review the opinion of the analysts. These individuals closely follow the data and have unhampered access to top medical advisors
8. Revisit step 3 and now search Phase I trials*. Then re-do step 4-6.

*Remember, under normal circumstances, one would prefer to enroll in a trial that is at a higher phase than another (i.e., Phase III vs. Phase I) due to the accumulation of scientific data to date.

9. Return to www.clinicaltrials.gov website (homepage). Initiate a new search but now enter only your 'general' cancer into the search box. (i.e.- soft tissue cancer). There will be a lot more trials available.
10. Repeats all steps again. These results MAY be considered as a lower priority behind the previous trials since drugs in these studies may be investigated for multiple cancers/subtypes and not simply specific to yours.
11. IMPORTANT: It is not the time to begin looking for additional trial opportunities after a patient fails on one. It is appropriate to meet with your physician and recognize that a trail enrollment strategy should be preplanned. Yes, deviations will often occur depending on how you respond to a previous trial however the time between failure on one trial and enrollment in the next should never exceed the mandatory thirty-day wash out period. One must have a discussion on a number of viable trial opportunities with their physician before enrolling in the first. Before discussing these trials with your physician, call the trial sites to determine how long they will be enrolling patients. If two trials look equally promising but one trial is nearly for closed for enrollment due to capacity issues while the other is just beginning enrollment, one may use this knowledge to shift or predetermine your priority order in which to enroll.
• Caregivers- you do not need to share this with the patient as it may be considered pessimistic and negative to predict failure. I merely advocate that one hopes for the best results but is prepared for the worst. Additionally, it was a very powerful mood shift opportunity for my father to have with my mother on the ride back from the hospital day she learned that she was disqualified from her trial due to lack of efficacy. The ability for my father to now share a new trial he and my mother’s Oncologist discussed previously (and privately) helped to give her renewed optimism and a plan for the near future.
12. When you have your list of trials, your initial ranking should take into account the following:
• Phase of trial – Phase III has a higher probability of success than a Phase I.
• Manufacturer of the drug – Generally, a larger drug company is more likely to study a new compound/drug with greater promise than a small company might. Larger companies have much more resources at their means to rigorously test a proof-of-concept and compile more preclinical data. Additionally, larger manufacturers are more likely to have the “luxury of riches” whereby they must often twiddle down multiple compounds/drugs before determining the one they will put forward in a clinical trial. Smaller companies are often built around one drug candidate.
• Press/News around the drug – Is there a good bit of press on the drug. (i.e., drug presented at a society meeting like ASCOT; is it approved in Europe; is the drug a follow-on compound whose parent compound has shown excellent results?; etc.
• Targeted therapy – Is the drug in the trial targeted to your specific disease sub-type?
• Quality of Life – May include trial location, frequency of treatments/infusions, etc.

In summary, select a physician who specializes in treating your disease at a medical center that also specializes in treating your disease. Teaching hospitals usually have access to the most studies but there are certainly exceptions. There is no nobility in protecting the ego of a physician by not visiting other physicians. This is not an offensive act. You have the right and obligation to contact other physicians on your own behalf no matter how wonderful your treating physician is. If nothing else, this exercise will help to ratify those decisions your physician has already made and thus, bring you greater piece of mind. Also, other physicians may have access to trials that your treating physician does not. Above all, partner with your doctor to help him/her stay informed as to the best trials available for your condition. You bring them the information but let them ultimately decide. I hope you find some value in my suggestions. My parents had generally felt like my research may have extended my mothers’ life span several months longer than without. While I don't know this to be the case, I will certainly treasure every minute I had with my mother. I wish you an even better outcome. Please stay in touch.

Regards,

Jay Ross