From de-centralized clinical trials to real world data (RWD), real world evidence (RWE), and even social media, the future for clinical research at Pfizer sounds increasingly tech-enabled and focused on meeting and engaging patients where they are.
Pfizer’s Head of Clinical Trial Experience, Judy Sewards, and Head of Clinical Operations & Development, Rob Goodwin, drop in to chat about what Pfizer’s approach to clinical research looks like now, after the rapid evolution it underwent to “lightspeed” the development of the Covid-19 vaccine.
The big change? Rob says they are “obsessed” with de-centralized trials, with nearly 50% of clinical trial visits still happening virtually. And, beyond the convenience factor, both point to de-centralization as a critical factor in being able to recruit more patients into trials as well as improve the diversity of their participant groups. In the end, the decentralized approach, says Judy, is “not just a matter of equity, but good science as well.”
And what about improvements to the cost of drug development? Is it too soon to tell if de-centralization will make an impact on the bottom line? Innovation may be expensive to implement at first, but, explains Rob, “If you can recruit your trial faster, overall, the cost of development goes down and speed to the patient goes up.”
We chat through the full suite of benefits that de-centralized clinical trials are bringing Pfizer and its patient populations, and get into the utility of real-world data, which also saw new notoriety when the Covid-19 vaccine was being developed. How is RWD impacting clinical research even when it’s not being used as evidence in a regulatory approval process? Watch and find out more about how data innovation is shaping the future of pharma!
For community cancer centers that rely on patient reimbursement to stay afloat, a smart data-driven approach to clinical trials provides a foundation for future growth.
By TANDY TIPPS and BRENDA NOGGY
Covid-19’s tragic, devastating impact on cancer treatment is now well documented. Cancer screenings dropped by almost 90 percent at the peak of the pandemic. Billing for some leading cancer medications dropped 30 percent last summer. Studies found a 60 percent decrease in new clinical trials for cancer drugs and biological therapies.
Cancer centers, like every part of the US health system, have a lot of ground to make up. Those community cancer centers without grants and other institutional advancement funds, experience financial and human resources as major constraints to charting a path to growth. For them, successful programs which generate revenues for expansion or break even help them maintain fiscal health. Often, unfortunately, too often their research programs lose money.
Clinical trials have not been a viable revenue source because of the difficulty in accurately predicting patient enrollment and the challenges of managing trial portfolios, a task that requires streamlined feasibility processes that include querying baseline populations for new trials and potentially eligible patients.
The hard work of patient screening and trial matching requires clinical coordinators, physician investigators and research support staff to spend between three to eight manually scouring databases of electronic medical records and unstructured files to find patients eligible for trials based on increasingly complex inclusion and exclusion criteria. This costly process does not take into consideration the pre-screening efforts in patient matching that may not be reimbursable.
Resources are also needed to implement feasibility processes to accurately predict how many patients might enroll in a trial if they are eligible. Most community-based sites do not have an accurate ability to query their current patient populations by disease cohort or mutation in real time. They often rely on physicians’ memories to estimate patient numbers for trial feasibility questionnaires, which must returned to sponsors quickly, usually before cancer centers have definitive recruitment numbers.
As a result, before COVID, an average of only 5 percent of patients had a chance of participating in trials, 50 percent of clinical trials failed to meet enrollment goals and less than 14 percent were completed on time. Cancer centers still incur the administrative and clinical resources required to maintain the protocols in the first place, however.
An email interview with the Co-CEO’s of Evidation Health
Over the last few weeks I’ve been conducting a back & forth email interview with Christine Lemke (L) & Deb Kilpatrick (R), the co-CEOs of Evidation Health. They raised $153 million in a Series E back in March (almost a small round these days!) but I wanted to understand a bit more about what the “new” Evidation was doing—Matthew Holt
Matthew Holt: Congrats on the latest funding. Clearly Evidation has evolved since its founding, but focusing first on the clinical trial study aspect, can you explain how the Achievement panel is structured? How was it put together? What are the typical ways that your clients use it, and what is the member experience?
Deb Kilpatrick: Our Achievement platformis the largest virtual connected research cohort in the United States, with more than 4 million users across all 50 states and representing nine out of every 10 ZIP codes. Through the platform, accessible via our app or through a browser, individuals have the opportunity to contribute to ground-breaking medical research in a number of ways: they can connect smartphones, wearables, and connected devices—think Apple Watches, Fitbits, CGMs, etc—that generate heart rate, activity, sleep quality, and other health-related data; they can connect health apps like Strava and MapMyFitness; and they can participate in surveys and provide patient-reported outcomes (PROs) of many forms.
And they do so with strong privacy protections for both data collection and data use, including use-case specific consents that can be sequential over time. This goes for new Achievers and those who have used the platform for years. And Achievers always have the option to remove themselves from any research project, and/or the platform altogether, at any time.
What do we do with that data? Evidation partners with leading health care companies, including nine of the top 10 biopharma companies in the world, to understand health and disease outside the clinic walls while measuring real world product impact. We’ve conducted virtual trials for almost a decade now, totaling more than 100 real-world studies across therapeutic areas.
One harsh Chicago winter, I remember calling a patient to cancel his appointment because we had deemed it too risky for patients to come in for routine visits—a major snowstorm made us rethink all non-essential appointments. Mr. Z was scheduled for his 3-month follow-up for an aggressive brain lymphoma that was diagnosed the prior year, during which he endured several rounds of intense chemotherapy. His discontent in hearing that his appointment was canceled was palpable; he confessed that he was very much looking forward to the visit so that he could greet the nurses, front-desk staff, and ask me how I was doing. My carefully crafted script explaining that his visit was “non-essential” and “postponable” fell on deaf ears. I was unprepared to hear Mr. Z question: if this is his care, shouldn’t he be the one to decide what’s essential and what’s not?
This is a question we are all grappling with in the face of the COVID-19 pandemic. The healthcare industry is struggling to decide how to handle patient visits to doctor’s offices, hospitals, and imaging centers, among others. Elective surgeries are being canceled and advocates are arguing that non-essential outpatient and ER visits should be stopped. Ideas are flying left and right on how best to triage patients in need. Everyone has an opinion, including those who ironically consider themselves non-opinionated.
an oncologist, these various views, sentiments, tweets, and posts give me
pause. I understand the rationale to minimize patients’ exposure and thus prevent
transmission. However, reconsidering what we should deem “essential” has made
me reflect broadly on our method of providing care. Suddenly, physicians are
becoming less concerned about (and constrained by) guidelines and requirements.
Learning how to practice “essential oncology” may leave lasting changes in our
Every so often, my cynical self emerges from the dead. Maybe it’s a byproduct of social media, or from following Saurabh Jha, who pontificates about everything from Indian elections to the Brexit fiasco. Regardless, there are times when my attempts at refraining from being opinionated are successful, but there are rare occasions when they are not. Have I earned the right to opine freely about moving on from financial toxicity, anti-vaxers, who has ‘skin in the game’ when it comes to the health care system, the patient & their data, and if we should call patients “consumers”? You’ll have to decide.
I endorse academic publications; they can be stimulating and may delve into more research and are essential if you crave academic recognition. I also enjoy listening to live debates and podcasts, as well as reading, social media rants, but some of the debates and publications are annoying me. I have tried to address some of them in my own podcast series “Outspoken Oncology” as a remedy, but my remedy was no cure. Instead, I find myself typing away these words as a last therapeutic intervention.
Here are my random thoughts on the topics that have been rehashed & restated all over social media outlets (think: Twitter feeds, LinkedIn posts, Pubmed articles, the list goes on), that you will simply find no way out. Disclaimer, these are NOT organized by level of importance but simply based on what struck me over the past week as grossly overstated issues in health care. Forgive my blunt honesty.
Keynote speech on the JAVELIN not going far enough to improve survival
The treatment landscape for metastatic renal-cell carcinoma has changed dramatically with the introduction of immunotherapies. Unfortunately though, we are promoting combinations over single agents without having much idea of added benefit of each drug. This is an important issue because when we combine two drugs, the only thing we are certain of are the added toxicities. PD-1 inhibitor nivolumab had improved OS when given in second line, however nivolumab was tested in combination with ipilimumab (not as a nivolumab monotherapy) in the first line trial. Now, pembrolizumab and avelumab have followed suit, although their combination partner was axitinib – a VEGF inhibitor. The control arm was sunitinib for both of the trials of pembrolizumab plus axitinib (KEYNOTE 426) and avelumab plus axitinib (Javelin 101). This is a little surprising because we are testing A B versus C, where both A and B haven’t been approved for the given setting – axitinib was approved for RCC in second line. Both these combinations improved PFS versus sunitinib but only the pembrolizumab combination has shown improved OS. However, I have doubts about the contribution of axitinib to these results. What would the outcome be if pembrolizumab alone is followed by sunitinib in second line? It is important to note that only one third of patients who discontinued sunitinib received PD-1 inhibitor subsequently in the KEYNOTE 426 trial. The important question for patients and clinicians would be to consider a survival difference had most of these patients received a PD-1 inhibitor subsequently. As for avelumab, the JAVELIN trial hasn’t reached as far as pembrolizumab and nivolumab have reached: The OS benchmark – so let’s reserve this combination until we see that benefit.
Have we successfully landed on the COMET?
We should remember that this combo-mania with PD-1/PD-L1 inhibitors may also backfire. Previously, the RCTs of nivolumab and pembrolizumab combos were halted in multiple myeloma for higher deaths in the combo arms. Another RCT IMblaze 370 also reports that atezolizumab, alone or in combination with cobimetinib, failed to improve survival versus regorafenib in patients with metastatic colorectal cancer. This time again A B failed versus C although C in itself is a drug with very marginal benefits in this setting. Also, I don’t understand testing A plus B combo when both A and B are unapproved for the disease.
Well, you might not have noticed that my blogs were missing for the last three months but anyways, its good to be back. I was having a little time off blogs and social media as I was transitioning in my career but now I am back. Sometimes, it is very difficult to manage time for things that you must do versus things you enjoy doing, especially when these two don’t intersect. For me, these last few months the things I had to do were all bureaucratic while I couldn’t find the time for things I enjoy doing like writing these blogs. But now that we are back, let’s recap what has happened in the oncology world in the year 2019 so far. I can’t cover all of them, but will try to summarise the major events in oncology.
Hundred Foxes’ Howl versus One LION’s Roar
In my country, there is a saying that goes somewhat like the roar of one lion will scare hundreds of howling foxes away. In medicine, I guess, it translates as one good RCT trumps the results from hundreds of observational studies. For patients with advanced ovarian cancer, primary surgery to achieve complete resection is the most important treatment and prognostic factor. However, what to do with the lymph nodes is a question that has troubled the oncology community for a long time. Logically, it makes sense to remove the lymph nodes too because they are the sanctuary sites for cancer cells. However, lymph node dissection carries high morbidity. Although multiple observational studies suggested a survival benefit with lymph node dissection, the LION trial, now published in the NEJM, shows that for women with macroscopic complete resection of primary tumour, lymph node dissection increases morbidity (postoperative complications) and post-operative mortality rates but doesn’t improve survival. I am glad that this trial was carried out and these results will now save many women with ovarian cancer worldwide from unnecessary harmful procedures, but I am also sad that we didn’t answer this question until now and thus, many patients suffered unnecessarily. I hope this LION’s roar scares us from jumping to conclusions based on logic or observational data alone and without RCT evidence in future. Another lesson here is the importance of public funds in supporting RCTs like these.
September was an important month in oncology—especially for lung cancer. The World Conference in Lung Cancer (WCLC) 2018 gave us some important practice-changing results, also leading to four NEJM publications. The trial with most public health impact is unfortunately not published yet. It’s the NELSON trial that randomised more than 15000 asymptomatic people at high risk of lung cancer to either CT-based screening for lung cancer or to no screening and found a significant reduction in lung cancer mortality rates among the screened cohort compared with the control cohort. This reduction was more pronounced among women, although they constituted only 16% of the trial population. I am looking forward to reading the full publication and am particularly interested in knowing if there were any differences in all-cause mortality rates and the rates of overdiagnoses.
A new ALK-inhibitor on the block—brigatinib—has significantly improved PFS versus crizotinib when used as first-line therapy in ALK-positive non-small cell lung cancer (NSCLC) patients. However, I assume that it will be difficult for brigatinib to replace alectinib in this setting, since the latter has already been tested in two different RCTs and has more mature data.
With Keynote 407, pembrolizumab has entered into the treatment arsenal for squamous NSCLC by improving overall survival in combination with chemotherapy versus chemotherapy alone as a first-line regimen. However, when A B is compared with A, it is important to know whether A B is better than A followed by B. In this trial, 32% of patients who were in the control arm received a PD-1 inhibitor upon progression. Nivolumab is already approved as a second-line option in this setting after first-line chemo; so how much benefit in Keynote 407 is due to more than half of control arm patients not getting PD-1 inhibitor at all versus the benefit of combining pembrolizumab with chemo upfront is an important question.
There was a very sobering piece in NEJM by the FDA last month in which the authors try to explore what went wrong with the Keynote-183, Keynote-185 and checkmate 602 trials testing PD-1 inhibitors combinations with pomalidomide or lenalidomide and dexamethasone in multiple myeloma. Interim analysis of Keynote 183 and 185 revealed detrimental effects on overall survival (OS) with hazard ratios of 1.61 and 2.06, not explained by differences in toxicities alone. The checkmate 602 trial was also halted in light of these findings and also showed higher mortality in the nivolumab combination arm.
In the thoughtful NEJM piece, the authors make at least three important points. First, they question why these PD-1 inhibitors were tested in combination despite their having limited single-agent activity. In fact, a couple of years ago, Vinay Prasad and I asked the same question: why are novel cancer drugs being tested in combination despite having limited activity as a single agent? We found that these drugs, even when ultimately approved, provide relatively low value and recommended that drugs with poor single agent activity not be tested in combinations unless there are specific reasons to expect synergy.
The second important point in the article is that many cancer drug approvals are lately based on durable response rates in single arm trials without a control group, a situation in which it is difficult to evaluate the safety and efficacy of drug combinations. Indeed, without an RCT, the oncology community would never have known these signals of detrimental effect. If the FDA had approved these PD-1 inhibitors in multiple myeloma on the basis of non-randomized trials, which it often does in other oncology contexts, who knows how long it would have taken to recognize the increased mortality in patients—and at what cost. This is another reason why we need RCTs more now than ever. Finally, the authors point out that these PD-1 inhibitors in multiple myeloma were directly advanced to phase 3 trials after phase 1 trials were completed, without phase 2 information. Indeed, in a recent paper, Alfredo Addeo and I showed that a substantial percentage of drugs that fail in phase 3 trials do not have supporting phase 2 data. Continue reading…
In April 2016, I published guidance, in the form of a mock case study, on how to access a drug before it has been approved by the FDA—what’s known as pre-approval (or expanded or compassionate) access. This is an updated version of that guidance, reflecting multiple important changes in the pre-approval landscape over the past year. In particular, the FDA rolled out a new, streamlined form for single-patient requests, and Congress passed the 21st Century Cures Act, which, among many other things, mandated that certain pharmaceutical companies provide public information about their pre-approval access policies.
Patients (and physicians) trying to access an unapproved drug outside of a clinical trial can feel as though they’re navigating uncharted waters. Many physicians don’t know that the FDA permits the use of unapproved drugs outside of clinical trials; those who do know often have no idea how to access such drugs for their patients. Those physicians who know about pre-approval access are largely specialists in certain areas—often, oncology or rare diseases—and they are generally self-taught: they didn’t learn about pre-approval access in medical school or in their residencies. Thus, while some physicians have become very accustomed to requesting pre-approval access to drugs, the majority lacks this knowledge. In this essay, I use a fictional case to trace the process for requesting access to an unapproved drug. I hope to explode several myths about the process, especially the beliefs that the FDA is the primary decision-maker in granting access to unapproved drugs and that physicians must spend 100 hours or more completing pre-approval access paperwork.
Imagine you are a physician, and you have a pregnant patient who has tested positive for the Zika virus. She is only mildly ill, but she’s terrified that the virus, which has been linked with microcephaly and other abnormalities, will harm her unborn child. She’s so concerned that she is contemplating an abortion, even though she and her husband have been trying to have a child and were overjoyed to learn she was pregnant.