The availability of point of care antibody testing—also known as serological testing—may provide a feasible roadmap for getting people back to work safely following the COVID-19 crisis, according to an editorial published in the journal Contemporary Clinical Trials Communications.

“You can’t stop the economy forever,” asserted Governor Cuomo in a recent news conference, according to STAT. “So we have to start to think about, does everyone stay out of work? Should young people go back to work sooner? Can we test for those who had the virus, resolved, and are now immune, and can they start to go back to work?”

Regardless of whether they already have immunity to the virus, millions of Americans may try to return to work, potentially undoing all the benefits of the shutdown, suggests the editorial. 

Antibody testing, the authors argue, could clarify a person’s status quickly in real-time and reveal whether they have been exposed to COVID-19. Accordingly, a person who mounts an IgG positive response (suggesting the presence of immunoglobulin G antibodies) would most likely now be immune to the virus and an IgM positive result would point to the process of developing immunity in someone who more recently became infected.

“Unlike the PCR tests (a measure of virus material), the immediate results and unconstrained supply of antibody tests could fundamentally change the way we manage this epidemic,” says Robert Jackson, MD, a co-author of the paper. “And from an economic perspective, it could lead to a tractable path for people to return to work. Collecting the data and tracking individuals longitudinally, in order to confirm the hypothesis, will be necessary.”

And barring any HIPAA concerns, the authors propose that persons with positive antibody tests during periods of social distancing could get a bracelet, which indicates that they are immune-protected and can return to work. Those without a bracelet would still be asked to practice social-distancing and not yet resume their normal activities. But this approach could potentially get at least some portion of the economy back running again, suggests the authors.

According to the authors, the antibody tests are cheap, easy to administer, and could be made available at every hospital.

“Broad testing is in society’s best interest,” says Alex Karnal, a co-author of the editorial. “Until we make serological tests available in a robust way, it’s as if we are flying a plane without navigation.”

Authors of the editorial, titled, “Let’s Get Americans Back to Work Again,” are: Alex Karnal, Partner and Managing Director; Robert Jackson, MD, Partner and Chief Science Officer; and Joe Pearlberg, MD, PhD, Vice President of Scientific Affairs, all at Deerfield; and Amitabh Chandra, PhD, McCance Family Professor at Harvard Business School and Weiner Professor at the Harvard Kennedy School.

Despite Evidence Showing the Opioid Crisis Disproportionately Affects Rural Areas, Prescriber Growth There Remains Considerably Slower 

While there has been an uptick in the number of U.S. clinicians having waivers to prescribe the potentially life-saving drug, buprenorphine, the total number of waivered prescribers in 2017 still represented fewer than 10 percent of all primary care providers, found a report published online in the January 7 issue of the Annals of Internal Medicine.

Moreover, although rural communities have been shown to be disproportionately affected by the opioid epidemic, the growth in the number of providers having this required certification there remains strikingly low, compared to more urban areas. Authors from the RAND Corporation suggest a need for more targeted efforts to increase access to the medication.

To assess the growth in buprenorphine-waivered providers by region and demographics, the investigators leveraged insights from analysis performed by the Deerfield Institute.

Tapping population estimates from the 2010 U.S. census and total physicians per capita, the researchers calculated the total number of waivered providers per 100,000 from 2007 to 2017. Statistics from the Census Bureau were also used to determine per-capita sociodemographic characteristics.

Over the decade studied, the researchers found that the number of waivered providers, in general, increased from 3.80 to 17.29 per 100,000 persons. Growth rate of waivered providers was markedly slower in small, nonmetropolitan areas, as it was in communities with lower levels of education.

The Food and Drug Administration approved buprenorphine for treating opioid dependency in 2002. According to Kaiser Health News, once physicians secure the waiver, they can prescribe buprenorphine in a range of settings, including primary care offices, community hospitals and correctional facilities. Compared with methadone, Buprenorphine is less likely to result in fatal overdoses.

The federal government is undertaking a number of efforts to increase the amount of buprenorphine prescribers.

More details on the research may be found here: Annals of Internal Medicine.

The authors of the paper are Ryan K. McBain, PhD, MPH, Andrew Dick, PhD of the RAND Corporation in Boston, Massachusetts and Mark Sorbero, MS, and Bradley D. Stein, MD, PhD of the RAND Corporation in Pittsburgh, Pennsylvania.

Real-time feature of Acutus’ AcQMap results in improved patient outcomes

A clinical trial investigating Acutus’ AcQMap showed that this novel imaging and mapping system safely guided cardiac ablation resulting in a 12-month freedom from recurrent atrial fibrillation (AFib) in 73 percent of patients with persistent atrial fibrillation.

The results, published in the July 1, 2019 issue of the Journal Circulation: Arrhythmia and Electrophysiology were first reported earlier this year in a late-breaking trial at the 24th Annual AF Symposium in Boston.

Known as UNCOVER-AF, the trial prospectively studied the safety and efficacy of the AcQMap in 127 patients at 13 sites in Europe and Canada – 98 percent of whom achieved a normal heartbeat upon completion of the procedure.

Characterized as an irregular heartbeat, AFib is the most common type of heart arrhythmia and could greatly increase a person’s risk of developing a severe stroke. Cardiac ablation is a procedure that can reduce the risk, yet traditional ablation procedures often fail to achieve long-term absence of AFib, resulting in repeat ablation procedures.

With its precision ultrasound and high definition re-mapping capabilities, AcQMap helps inform physicians in real time who can strive to improve outcomes by checking their work after each ablation.

Adapted from Acutus’ news release: Publication of UNCOVER AF Study in Circulation Demonstrates Impact of Charge Density Mapping During AF Ablation

Acutus has been a Deerfield portfolio company since 2016.  

Farapulse PFA shown as potential alternative to existing ablation procedures

A method of non-thermal field ablation demonstrated safety and efficacy in clinical trials comparing outcomes of the modality to those seen with traditional thermal approaches in patients with paroxysmal atrial fibrillation, or episodic AFib.

The results of the first-in-human trial were reported in an online early version of the manuscript that is slated to publish in the Journal of the American College of Cardiology.

Called pulsed field ablation (PFA), the alternate modality was shown to successfully target heart tissue without damaging adjacent structures like the esophagus or phrenic nerve – a shortcoming of standard ablation therapies, including radiofrequency (via heat) and cryotherapy (by way of freezing).

In 81 patients, 100% of pulmonary veins (PV) were specifically isolated with three minutes of PFA time per patient. Furthermore, long-term remapping procedures demonstrated that the rates of durable PV isolation improved with successive waveform modifications with the most optimized PFA group demonstrating 100% durability.

The rate of primary safety events was low at 1.2%, and with no subsequent primary adverse events during follow-up.

Farapulse has been a Deerfield portfolio company since 2017.

In research that could potentially help increase the efficiency of drug development and support precision medicine, Ming Zhu, PhD, identified ways to further enhance FDA-proposed enrichment strategies. Ming presented his findings in early July at the International Chinese Statistical Association (ICSA) conference in China.

In an effort to improve efficiency of drug trials, the FDA first created its enrichment strategy guidelines in 2012.

The FDA defines enrichment as the “prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population.” Examples of patient characteristics include demographic, pathophysiologic, historical, genetic or proteomic, clinical and psychological.

As a part of his analysis to inform on potential areas for strengthening these guidelines, Ming compared the enrichment strategies employed in several clinical trials, while closely reviewing and factoring in the respective study design, the statistical analysis used, along with lessons learned from the trial’s success or failure.

Among Ming’s recommendations are determining the suitability for the disease area in question, adapting quickly from previous studies and enhanced communication with regulatory agencies, when considering an enrichment strategy.

With regard to adapting quickly, Ming discussed a successful phase 3 trial that had benefited from information just released from another trial, pointing to the importance of staying abreast of and acting quickly on related, emerging evidence. In this example, the newly reported data informed on the enrollment of a more enriched study population for the current trial.

Ming emphasized that having early and open communications with regulatory agencies are critical for sponsors in order to secure endorsement of the planned enrichment strategies and statistical methods before undertaking the pivotal trials. As a case in point, Ming cited successful clinical programs that progressed all the way to regulatory submission, only to be rejected when the agency found the enrichment strategies applied to be unacceptable.

He hopes that his research will provide helpful insight into enrichment design and guidance for clinical investigators to develop appropriate strategies toward improved probability of success of clinical trials.

V-Wave, Ltd., recently announced that it received the prized FDA Breakthrough Designation for its heart failure shunt. Breakthrough designation is one of the highly sought pre-approval stamps that the FDA can place on a device.

According to the FDA’s website, it is granted when the device “provides for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions” (than what is currently available). The program aims to provide patients and health care providers with more timely access to medical devices “by speeding up their development, assessment and review,” including prioritized review all the way through to market approval.

V-Wave’s minimally-invasive implanted interatrial shunt for the treatment of patients with severe symptomatic heart failure is designed to regulate left atrial pressure, the primary cause of breathing difficulty and hospitalization due to worsening heart failure.

“In addition to validation of the potential impact of this technology, breakthrough status will facilitate a timely regulatory review and solve a major issue with medical device investments, namely that reimbursement will effectively be secured immediately upon approval,” said Deerfielder, Andrew ElBardissi, MD, who serves on the Company’s board of directors.

The shunt is currently being evaluated in a global, randomized, controlled, double-blinded, 500 patient pivotal Investigational Device Exemption trial called RELIEVE-HF. The study is enrolling advanced heart failure patients with preserved or reduced left ventricular ejection fraction who

remain symptomatic despite the use of guideline directed medical and device therapies.

An ejection fraction is an important measurement of how well the heart is pumping and is used to help classify heart failure and guide treatment. In a healthy heart, the ejection fraction is 50 percent or higher – meaning that more than half of the blood that fills the ventricle is pumped out with each beat.

According to the Centers for Disease Control and Prevention, nearly 6 million adults in the United States have heart failure and about half of these individuals die within 5 years of diagnosis. Heart failure costs the nation an estimated $30.7 billion each year.

Achieving this status means that the device also met at least one of the following FDA criteria:

1. It represents breakthrough technology;
2. No approved or cleared alternatives exist;
3. It offers significant advantages over existing approved or cleared alternatives; and
4. Availability of this device is in the best interest of patients.

V-Wave, Ltd., a privately held medical device company, has been a Deerfield portfolio company since 2018.

Adapted from company news release: V-WAVE’S INTERATRIAL SHUNT RECEIVES FDA BREAKTHROUGH DEVICE DESIGNATION FOR HEART FAILURE:

https://www.fda.gov/medical-devices/how-study-and-market-your-device/breakthrough-devices-program

https://www.mayoclinic.org/diseases-conditions/heart-failure/symptoms-causes/syc-20373142

https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm

In a past issue of this newsletter (September 2017) we took a broad look at the salient issues pertaining to the realm of biosimilars, including regulatory, legal, and commercial aspects of the debate. We refer readers here for an initial grounding if needed.  In the intervening time period, new developments have played out that highlight the significant barriers to commercial uptake that exist for these products.

Briefly, biosimilars are to biologics as branded drugs are to generics. However, both biologic drugs and biosimilars are by and large exceedingly more difficult to manufacture and thus bring to market as the production process is critical to the potency and release quality of these drugs within parameters established by the innovator product.  There are only yet 15 biosimilars approved in the US, and only five are actually commercially available, with the remainder being still blocked from the market due to patent exclusivity.  Contrast this to Europe, where 40 biosimilar products are approved.   

The cost of production for these products is not nearly at the level of generics. Take insulin, for example.  Insulin has a somewhat hybrid role in the US, as the first formulations were approved before the biologics approval pathway existed in the US, so its “biosimilars” are approved under what is known as the 505(b)2 pathway in the US, as opposed to the 351(k) pathway used by products whose innovator products are a true biologic (as determined by approval pathway). The market would seem ripe for a Lantus biosimilar, as the product has greater than $4bn in annual sales. Eli Lilly already has a biosimilar to Lantus on the US market, called Basaglar, which is annualizing greater than $600m through its first six quarters into launch.

Merck, through a collaboration with Samsung Bioepis had a tentatively approved biosimilar to Lantus from July 2017. However, a filing by Samsung Bioepis in October 2018 indicated Merck had cancelled development and commercialization contracts for the product. One analyst report cited the decision to pull out as being due to a review of the market environment and production costs of insulin biosimilars.  If a biosimilar as relatively “simple” as insulin can be difficult to manufacture at scale with attractive margins, then this certainly cannot bode well for more complex protein products to do the same. With Merck’s exit, only Mylan, in collaboration with Biocon, is developing another Lantus biosimilar. While district court litigation is ongoing, a launch for Mylan and Biocon’s product is expected in the 2020-2021 timeframe.

Similarly, Momenta recently announced it would be cutting its biosimilar efforts altogether, and simultaneously cutting half its staff while it refocuses on its non-biosimilar pipeline.

It’s a (rebate) trap

FDA Commissioner Scott Gottlieb further shed light on another major commercial obstacle for biosimilars, dubbed the rebate trap, in a March 2018 speech at the America’s Health Insurance Plans National Health Policy Conference[1]. The deep discounts offered on certain branded specialty drugs (often biologic), in the form of rebates and other payment or contractual mechanisms, in many instances can be upwards of 40% to attain preferred formulary positions from pharmacy benefit managers (PBMs) and health insurers. Often these negotiated discounts are volume-based, so the greater the utilization over competitive products, the greater the spread from the wholesale acquisition cost (WAC) to the net price to the plan, with PBMs and health insurers earning a percentage of the spread. Launched biosimilar products have generally been introduced to the market with roughly 15-20% discounts to the WAC of originator products, and thus are unable to displace the originator product. Biosimilars get stuck in a catch-22 situation, where they lack enough patient share for plans to consider moving them to a better formulary position but are hindered from getting more meaningful market share while they sit on a lower formulary tier. PBMs remain financially incentivized to limit the uptake of biosimilars to maintain the flow of rebate payments on originator products. Simply further discounting the biosimilar so that the WAC is on par with the net price of the originator is easier said than done for reasons noted earlier, namely that these drugs have turned out to be much costlier to develop and manufacturer than earlier predictions.

PBMs are attempting to move past the bad press they have received around the rebate trap and the general practice of collecting rebates. Express Scripts recently announced the launch of its Flex Formulary, which will consider authorized generics of branded drugs for inclusion on the formulary, in either a preferred or non-preferred position, and, importantly, discontinue coverage of the branded product. This could foreseeably open the door to more biosimilar adoption on this formulary.  The first products added to the Flex Formulary were Epclusa and Harvoni, two hepatitis C drugs made by Gilead Sciences. 

Humira in the hotseat

Gottlieb has gone so far as to suggest a competitive bidding scheme for biologics would be ideal[2], which is more akin to the experience in the EU. For example, Remicade sales have fallen over two-thirds in the three years since the introduction of its first biosimilar in the EU. Another closely watched drug is Humira, the world’s top-selling drug, as four biosimilars have just launched in the EU. One analyst report has said AbbVie, the maker of Humira, has won its first tender in Europe by offering an 80% discount off the price prior to the launch of biosimilars[3]. The deep discounting shows the extent to which the company is willing to go to hold onto market share.

Humira biosimilars in the US are still a pipedream, protected by a patent thicket the company has created with additional patents on formulations changes and extending life as new indications are approved. AbbVie has forged confidential legal settlements with several biosimilar makers, that will keep biosimilar copies of Humira at bay until 2023. In the meantime, AbbVie and Amgen are likely to continue to find themselves under increased scrutiny over the practice of repeated price increases for their top-selling drugs. A recent article cited nearly a 140% overall price increase for both of those drugs since January 2013[4]. Without biosimilar competition, and assuming continued price increases on par with recent history, both drug makers could see themselves in the hot seat in the court of public opinion.

[1] https://www.fda.gov/NewsEvents/Speeches/ucm599833.htm

[2] https://www.fda.gov/NewsEvents/Speeches/ucm613452.htm

[3] https://www.statnews.com/pharmalot/2018/11/01/abbvie-humira-biosimilars-prices/

[4] https://www.statnews.com/2018/11/14/humira-abbvie-amgen-enbrel-price-hikes-biosimilars/

In the case of another historic first in the world of healthcare, this summer saw the first US and EU regulatory approvals for an RNA interference (RNAi) therapeutic, in the form of Alnylam’s Onpattro (patisiran). The drug, given as an infusion, was approved to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. A rare and often fatal disease, hAATR is characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart, and other organs. Up until this approval, the American College of Cardiology’s recommendations for treatment were merely supportive care and clinical trials, pointing to the level of unmet need for this patient population[1].

Still, it has been anything but smooth sailing for Onpattro, nor for the field of RNA-based medicines.  Like gene therapy, it has seen an earlier wave of enthusiasm come crashing down in the wake of technical challenges and safety issues. While Onpattro will not be a panacea to all the known issues, it is important to note where and how it has succeeded where others have failed and to understand what it means for other candidates in the pipeline. 

How it works

To understand how RNAi works, transport yourself to your high school biology class where you learned about the “central dogma” theory that explains the relationship between DNA, RNA and proteins – that DNA in the nucleus forms genes which are the template for transcription to RNA, which in turn is the template for translation to proteins. Those proteins then serve as a central player in most biological systems. In individuals without hAATR, the liver produces the TTR protein, used to transport vitamin A and a thyroid-binding protein in the body. Patients with hATTR have a mutation in the gene for TTR, which leads to the creation of a defective and unstable TTR protein. Onpattro binds to the mutated mRNA sequence that causes the defective protein, and cuts out that sequence, effectively halting the production of the misfolded and defective protein[2]. Of note, this approach targets the upstream cause of the defect, and not simply the downstream symptoms that are the manifestation of the defect.

Location, location, location

RNAi does not simply work by targeting the mutated mRNA of interest – it must additionally be specifically targeted to the tissue(s) of interest, which is the tougher nut to crack. The liver, the target organ of interest in hATTR, happens to be better suited for targeted drug delivery given its unique vasculature – notably that it has both the hepatic artery and hepatic vein, allowing it to effectively double dip on whatever has been infused into the blood stream, compared to other organs. It will be more challenging to deliver RNAi to other organs, which thus far has been a challenge to do at therapeutically appropriate levels. 

Onpattro is encased in a lipid nanoparticle to help carry the drug to the liver and enter the cell.  The lipid nanoparticle disrupts the cell membrane to allow Onpattro in to the cell, and thus can trigger an immune response, so patients must prophylactically take a steroid, acetaminophen, and antihistamines. There is thus also the need to find delivery vehicles that are slightly more sophisticated to obviate any immune responses.

How did we get here?

Pharma entered the RNAi fray in the early 2000s with some big dollar risk-taking in a hot field that would go on to earn a Nobel prize for its scientific discoverers, only to encounter future obstacles. Novartis and Roche paid their way into accessing Alnylam’s platform in 2005 and 2007, respectively. Merck paid $1.1bn to acquire Sirna Therapeutics, Alnylam’s main competitor at the time. Prior to that transaction, Sirna had a research deal with GlaxoSmithKline as well.  Early attempts in ophthalmology and other liver targeted attempts encountered issues with RNA degrading before reaching its target, and thus required extremely high dosing to show any efficacy. Novartis and Roche parted ways with Alnylam in 2010, and Merck eventually sold Sirna IP to Alnylam in early 2014 at a massive discount to its earlier purchase. In the interim, Alnylam soldiered on with some restructuring and a deal with Sanofi dating back to 2012 that helped keep it afloat[3].

Looking ahead

Alnylam has said the list price for one year of treatment in the US is $450,000 and has at least one value based agreement, with Harvard Pilgrim Health Care.  It plans to officially launch Onpattro later this year and will face competition in the US from Ionis and Akcea’s also newly approved Tegsedi (inotersen), and possibly also Pfizer’s Vyndaqel (tafamidis) before the end of this year.

Alynlam and others are pursuing experimental RNAi treatments in other indications, including acute hepatic porphyrias, cardiovascular disease, hepatitis B, alpha-1 antitrypsin deficiency, primary hyperoxaluria, delayed graft function, and alcohol use disorder[4]. Notably, several of these are also liver-targeted indications with various delivery methods to help with targeting.

[1]   http://blogs.sciencemag.org/pipeline/archives/2017/09/20/alnylam-breaks-through

[2]   https://www.fda.gov/Drugs/NewsEvents/ucm615953.htm

[3]   http://cienp.org.br/wp-content/uploads/2018/03/Alnylam-prepares-to-land-first-RNAi-drug-approval.pdf

[4]   https://www.wsj.com/articles/fda-approves-first-drug-based-on-gene-silencing-research-1533923359

Drug and device development requires extensive expertise, is costly, and time consuming. In particular, the need for deep expertise in many disciplines means there is a market value for those skill sets, and sometimes those exist in the private sector, but many times, in academia. The relationship between academia and industry is both praised and criticized, but unavoidable as increasingly complex diseases are tackled by both parties. As a result, many academics also have some kind of corporate relationship, be it as a trial investigator, a consulting or advisory role, or a speaker’s bureau slot, to name a few examples. As these relationships merit payment, critics feel industry payments erode away at academics’ ability to offer unbiased opinions and expertise, precipitating the need for some kind of disclosure.

Putting aside the details of the most recent example of a debate over conflict of interest (COI) out of Memorial Sloan Kettering Cancer Center (MSKCC), much of which has already been detailed elsewhere[1], the response suggests disclosure is not only preferred but necessary, though the who, how, and why have yet to be hammered out. Medical journals and some specialty societies may require the data, but do not have uniform criteria for the reporting of industry ties (whether by physicians or sponsors) nor a readily identifiable platform for prospective patients or industry observers to view what relationships physicians may have.

The most comprehensive source of information is the Open Payments database maintained by the Centers for Medicare and Medicaid (CMS).^[2] Applicable manufacturers and group purchasing organizations are required to annually submit relevant payment information to physicians and teaching hospitals to CMS, and CMS subsequently allows physicians and those hospitals to review the reported payments for accuracy. Payments for research, meals, travel, gifts, and speaking fees are all required to be reported.

While the most comprehensive, there are some notable exemptions to the Open Payment database, which some argue are loopholes asking to be closed. Companies that do not yet have a marketed product approved by the Food and Drug Administration do not have to report payments, meaning many small biotech companies working on their very first product are not reporting to the database.  Additionally, continuing medical education (CME) payments are also exempt, though some argue CME is simply another avenue for industry to market their new launches and pipelines.

Referring to the recent MSKCC news, medical ethicist Dr. Arthur Caplan publicly commented “We have yet to figure out what COI means or how to manage it in a health care world where industry ties are everywhere”^[3] which is likely the best succinct encapsulation of the status quo. It is unknown what payment threshold might influence physician decision making (whether perceived or actual), but there is also some intangible value to physicians who serve as investigators on cutting edge clinical trials and serve on advisory boards alongside the top minds in their fields, who in turn can provide better care for their patients. It would be wrong to suggest that all interactions between industry and physicians are either unethical or inappropriate, but we can, and should, do better at reporting them.

[1]   https://www.nytimes.com/2018/10/12/health/memorial-sloan-kettering-cancer-disclosure.html

[2] https://openpaymentsdata.cms.gov/

[3] https://twitter.com/ArthurCaplan/status/1038849711174762499

The entire paradigm of therapeutic and medical device development in the modern era is predicated on demonstrating safety and efficacy within parameters deemed appropriate by regulators like the Food and Drug Administration (FDA) and European Medicines Agency (EMA). This is proven in a series of clinical trials, known as Phase I to Phase IV studies, with each phase generally expected to demonstrate additional levels of data. This requirement for evidence generation via clinical trials contributes to the event driven nature of biopharma/medtech, creating somewhat predictable time points when sponsors can demonstrate added value in their programs with successful studies. The significance of a positive study to a share price or company valuation has had the unfortunate side effect of leading some sponsors to be less than 100% transparent in reporting the read-outs of trials, lest a hint of negative findings taint the remaining dataset. Below we lay out the archetypal road map of clinical trials and ways to be savvy to interpreting these.

General structure of clinical development programs

Phase I trials, sometimes known as first-in-man studies, are primarily meant to show the safety and pharmacokinetic profile (the onset, duration, and intensity of effect) of a novel therapeutic. These studies are traditionally done in healthy volunteers, and are typically not able to demonstrate efficacy. In areas like oncology, however, there may be phase I studies in actual patients that can look for preliminary signs of efficacy as well.

Phase II trials are conventionally dose-finding studies, and will test different dose levels, ideally to find the right therapeutic window of the drug, with the best combination of efficacy and safety. This can be done by taking an initial group of patients and slowly titrating up the dose of the drug over time until they experience adverse events, or by creating specified trial cohorts at different dose levels. Phase II results should importantly inform if it is even worthwhile to pursue Phase III, the costliest phase of development, or otherwise scrap a program. Once the best doses are selected from Phase II, sponsors then move on to Phase III.

The gold standard of Phase III trials is randomized, controlled, and double-blinded studies. Randomized means that patients who are enrolled in the study are divided, in a completely random fashion by someone other than the treating physician, into different arms or cohorts of the study. Controlled means that there is a comparator to the drug of interest. Comparators could be a placebo, a specific drug or regimen, or “best alternative care,” which may be any one of a series of different options determined at the physician’s discretion. The latter would be more common in studies where patients have already had multiple previous treatments. The double blinded nature of the study means that neither patient nor physician know what the dose of the administered drug (or placebo). This avoids introducing bias into the study. In the case of medical devices where a surgical procedure is required, trial protocols may call for “sham” procedures to maintain the blinded nature of the study. With any luck, a Phase III trial or trials will demonstrate the appropriate levels of safety and efficacy that allow the sponsor to submit for regulatory approval. There may be multiple Phase II and Phase III trials in a given development program, depending on the therapeutic area. Any one negative trial could kill an entire development program.

Sometimes, sponsors may have less than perfect data packages that they submit for regulatory approval. When there may be lingering questions about certain aspects of the drug or device, especially around things like long term safety, regulators may still approve the application, contingent on the completion of Phase IV or post-marketing studies, to make sure the worst fears are not borne out in use among larger populations. Also of note, trials are often conducted in “perfect” patients, who often look clinically very different from patients treated in real world settings that may have other co-morbidities, and be generally less healthy than trial patients. This makes the collection of longer term evidence more pressing, as either the number of severity of adverse events may vary in a real-world population compared to the trial population.

Understanding the general formats of data read outs

Sponsors have many outlets along the course of development to convey the results of trials to patients, health care providers, and investors. These range from something as simple as a press release, through poster and podium presentations at medical congresses, up to peer-reviewed publications in academic journals. Moving along that spectrum, there is increasingly more granular data, ideally shining a light on not only the good, but also the bad and the ugly.

The terse nature of press releases leaves them fraught with potential for ambiguity. At worst, sponsors may simply report positive efficacy trends, without noting the statistical significance as defined by a p-value, and with no mention of adverse events. The measure of efficacy can also be poorly defined; some questions a savvy reader should ask are^[1]:

• Is a positive signal from a primary endpoint or secondary endpoint? The primary endpoint is the most important hypothesis the trial sought to test.
• Was the p-value and form of statistical analysis associated with that endpoint prespecified? A prespecified statistical analysis is less vulnerable to selective p-value hacking once data has been unblinded.
• Were patients excluded from the efficacy analysis? If so, why? For example, is it just a particular subgroup or subgroups and not the entire enrolled population? Excluding patients may have the effect of only cherry picking the best-performing patients for the data analysis.

Moving up the chain, abstracts that are submitted to medical congresses as either poster or podium presentations are commonly peer-reviewed, albeit not with the same scrutiny that would come with a full journal article. These presentations typically have more details on the methods and results as compared to press releases. The public presentation of data by ether principal investigators or the scientists/clinicians driving a development program also provides at least some public venue for questions and answers.

There is a smattering of other outlets for partial data disclosure – these include corporate investor decks presented at investor conferences, so called “R&D days” hosted by companies, and sponsored satellite symposia at relevant scientific and medical conferences. These should generally be approached with the same caveats as above given the selective disclosure.

While it depends on the journal, the final publication of trial data is typically a much more robust and trustworthy source than the original press releases of the same data. Not only are there multiple authors on a given manuscript, many of whom are unlikely to be employees of the sponsor, there are also multiple peer reviewers, whom are experts in the same field and required as part the journal’s submission and editorial process. In addition, there are the journal editors themselves who are the final gatekeepers of the manuscript. In the event of particularly novel or noteworthy findings, journals may invite another key opinion leader in the same field to write an accompanying editorial to help put the findings, both good and bad, into perspective as part of the same journal issue. Often newly published articles may be open to comments from anyone interested in submitting them, which sometimes serve the purpose of poking holes in analyses or conclusions.

Full statistical plans and trial protocols may be included as appendices to the main journal article, which can be rich sources of information, but can be dense with jargon for non-experts. It is best to do a full read of not only the full manuscript but also those appendix items, and not simply rely on only the abstract or a third party summary, as these might be no better than the original press release. It is often a matter of years from the first press release to the final publication of the same data set.

Other trial designs

All of the above is based on very conventional clinical program designs, and there are some exceptions. For example, certain late stage cancers with a precision medicine biomarker, or other genetically defined rare diseases, have utilized much smaller clinical programs to gain regulatory approval, moving from a combined Phase I/II trial to a relatively small Phase III. This is due to the inability to recruit patients for large trials from a natural small pool, and in some cases, the highly targeted nature of the therapy allows for statistically significant demonstration of efficacy with a small trial size. There is also some interest in the use of basket trials to test the effect of one drug that targets a single mutation but in a variety of tumor types, or umbrella trials, that have many different arms within one trial. These designs come with different statistical considerations. Though the designs of clinical programs may vary, the platforms for presenting data are otherwise no different, and the same healthy dose of skepticism, if not more given the smaller trial sizes, should be applied to the interpretation of those results from press releases up to and including journal articles.

[1] https://www.sciencedirect.com/science/article/pii/S2451865416301132

Objectives

To quantify the approval, denial, and withdrawal rates and identify any predictors of success or failure for all new technology add-on payment (NTAP) applications from FY 2003 to FY 2018 in the United States.

Methods

The Center for Medicare and Medicaid (CMS) releases inpatient payment methodology rulemaking annually in the Federal Register, including details of NTAP submissions. The proposed and final rulemaking documents were analyzed to quantify the approval, denial, and withdrawal rates of all applications and determine primary reasons for denial or withdrawal from FY 2003 to FY 2018. Raw data were coded to further examine any predictors of application success such as product type, therapeutic category, manufacturer type, reapplication status, and proposed rule determination.

Results

There were 95 NTAP applications submitted over the last 15 fiscal years. Approximately 30%, 25%, and 45% of applications were approved, withdrawn prior to final rule, or denied, respectively. Inability to meet the “newness criteria” developed by CMS was the primary reason for denied and withdrawn applications. Product type, therapeutic category, and reapplication status have minor to significant impact on the approval rate of an application. However, manufacturer type and proposed rule determination have little to no impact on application outcome.

Conclusions

While there are a few factors that may positively influence the outcome of a NTAP application, the approval rates for the program are low overall. Without additional reimbursement from the NTAP program, inpatient hospitals may be deterred from adopting innovative therapies because of financial burdens. CMS and manufacturers should strive to find a better consensus for a framework that adequately incentivizes the utilization of new technologies for Medicare beneficiaries.