According to a press release issued by Onyx Pharmaceuticals, Inc. on October 25, 2011 a Phase 3 trial with regorafenib in metastatic colorectal cancer (mCRC) patients being conducted by Bayer HealthCare Pharmaceuticals met its primary endpoint of improved overall survival. Apparently, this trial’s independent Data Monitoring Committee conducted a pre-planned interim analysis and recommended that the study be unblinded and patients in the placebo arm be offered treatment with regorafenib. While no data has been made publicly available at this time, given the positive nature of the announcement we have expedited our review of this multikinase inhibitor. We are currently reviewing the published pre-clinical and early stage clinical trial data, as well as mCRC clinical epidemiology to provide clients with analytical support for organization specific reimbursement and list/don’t list formulary decisions.
We have completed our preliminary assessment of the FDA approved oncology drug ADCETRIS (TM) Brentuximab Vedotin using BioHorizon’s proprietary assessment methodology and have designated this oncology therapeutic agent as High Impact. Given the observed treatment effect in pivotal clinical trials we see potential for rapid uptake by oncologists responsible for treating the indicated patient populations. As with all High Impact therapeutics we recommend that our clients’ organization specific reimbursement and list/don’t list formulary decision making activities should be expedited. We will update client’s as more data becomes available.
On February 25th, 2010, Amylin, Lilly, and Alkermes announced in a press release that the FDA had set March 12th 2010 as the Prescription Drug User Fee Act (PDUFA) action date for Byetta’s long acting formulation – exenatide once weekly. Our readers will recall that Byetta is used by type 2 diabetics for glycemic (blood glucose) control and is administered subcutaneously twice daily. With an FDA decision imminent we thought it would be useful to review some of the salient points concerning this innovative therapy.
Similar to a class of compounds known as incretins (which includes glucagon-like peptide-1 (GLP-1)) Byetta is thought to exert its action by enhancing pancreatic beta-cell insulin secretion, suppression of elevated glucagon secretion, and the slowing of gastric emptying. In all three pivotal clinical trials supporting Byetta’s original approval body weight decreased at Week 30 in the 10 mcg treatment groups. We reviewed a 2008 Lancet article by Drucker et al involving 295 patients with type 2 diabetes which demonstrated that exenatide once weekly performed better in terms of glycemic control than exenatide twice daily over a 30 wk period with no increased risk of hypoglycemia.
Byetta, a first in class therapy, was approved in 2005 and was originally used as an adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sufonylurea, or some combination of the two and have not achieved adequate blood sugar control. In 2009 Byetta’ s indication was expanded to include its use as a stand alone or monotherapy in addition to diet and exercise to improve blood sugar control in Type 2 diabetes. Since the drug’s approval, safety concerns have arisen around the risk of acute pancreatitis with complications, including death and altered kidney function associated with Byetta use.
CDC data suggest that more than 1 000 000 Americans are diagnosed with diabetes annually and that there are in excess of 14 000 000 Americans currently afflicted with the disease. It is estimated that about 5 000 000 diabetics require daily insulin injections to control their blood sugars. Complications commonly associated with uncontrolled or poorly controlled diabetes include heart disease, stroke, kidney failure and blindness. Diabetes and its complications may account for more than $100 billion annually in healthcare costs in the United States.
At the risk of stating the obvious – we believe that if exenatide once weekly recieves FDA approval, simplification of the exenatide dosing regimen from twice daily to once weekly would be seen as very favourable by patients and physicians alike.
Thanks for reading.
The BioHorizon Health Technology Surveillance Update gives readers a concise, high level overview of the most important emerging health technology developments on a ongoing basis including key FDA approvals, substantive clinical trial results and upcoming events of importance.
First of all, on behalf of the entire BioHorizon staff, let me welcome you to the BioHorizon Health Technology Surveillance Update. Long time clients and readers will remember that Surveillance Updates last graced these pages in 2005-2006 and based on your feedback we have changed the focus of this feature to better meet your needs – we hope you agree!
Lets start by turning our attention to FDA approvals of note in January and February 2010. On January 11th, Genentech Inc.’s rheumatoid arthritis therapy, Actemra (tocilizumab), was approved for treatment of adults with moderate to severe rheumatoid arthritis who have not adequately responded to or cannot tolerate other approved drug classes for this disease. Serious safety concerns associated with this interleukin-6 blocker were cited as the basis for the FDA’s requirement for a post-marketing clinical trial to evaluate long term safety as well as a Risk Evaluation and Mitigation Strategy that directs Genentech to implement a communication plan for prescribing physicians detailing the appropriate approach to obtaining informed consent and side effect monitoring.
Acorda Therapeutics’ Ampyra (dalfampridine) extended release tablets were approved on January 22nd, to improve walking in multiple sclerosis patients representing the first drug approved for this use. The FDA cautioned that Ampyra can cause seizures when given at greater than recommended doses.
Turning to medical devices for a moment, Thoratec Corp.’s HeartMate II Left Ventricular Assist System was approved on January 20th for severe heart failure patients who are not acceptable transplant candidates. The HeartMate II was already approved for certain patients waiting for complex medical treatments including transplants. The FDA directed Thoratec to conduct a post-approval study to further characterize the device’s performance.
On January 25th, Novo Nordisk Inc got the nod for Victoza (liraglutide (rDNA) injection) the company’s once daily GLP-1 receptor agonist which is indicated for treatment of type 2 diabetes in adults and joins Eli Lilly’s twice daily Byetta in the injectable GLP-1 agonist class.
GlaxoSmithKline’s Tykerb (lapatinib) got an expanded indication from the FDA on January 29, and can now be used in combination with the Novarits product Femara (letrozole) in the treatment of hormone positive and HER2-positive advanced breast cancer in postmenopausal women for whom hormonal therapy is indicated.
And finally, on February 2nd the FDA approved Auxillium Pharmaceuticals’ injectable Dupuytren’s contracture therapy, Xiaflex (collagenase clostridium histolyticum) – this is the first FDA approved non-surgical therapy inidicated for this progressive hand disease.
We encourage our readers to visit www.fda.gov as well a company or product specific website for more details, in subsequent weekly updates we will begin to include some discussion of interesting clinical trial results from the week that was in additon to setting the table for the next week in emerging health technology. Thanks for reading.
These are interesting days for the first oral therapies targeting multiple sclerosis (cladribine and fingolimod or FTY720) indeed, with both positive and negative events making news over the last several weeks. On November 30th 2009, Reuters reported that the FDA had issued Merck KGaA a ‘refuse to file’ letter, which in effect is the FDA’s way of saying that the New Drug Application (NDA) is incomplete and we believe dramatically decreases any chance of a mid 2010 release date for this drug. On the flip side, and a more positive one, The New England Journal of Medicine recently published three articles detailing what in our view are very well executed clinical trials- two with fingolimod and one with cladribine. Given the high level of interest and some of the complexities we thought we would delve a little deeper.
Multiple sclerosis is a chronic, debilitating autoimmune disease that affects the brain and spinal cord. MS causes the body to direct antibodies and white blood cells against proteins in the myelin sheath that surrounds the nerves in the brain and spinal cord. This may cause inflammation and areas of scarring on nerves resulting in loss or decrease in function. An estimated 400,000 Americans have MS with about 2.5 million cases worldwide.
Current therapy for MS is focussed on prevention of relapses and/or slowing of disease progression using immunomodulatory drugs. FDA approved therapies include Avonex (interferon beta-1a IM ), Betaseron and Extavia, (interferon beta-1b SC ), Copaxone (glatiramer acetate SC), Rebif (interferon beta-1a SC), Novantrone (mitoxantrone IV) and Tysabri (natalizumab IV). Some analysts place worldwide expenditures on these drugs at greater than 8 billion dollars annually. Unlike fingolimod and cladribine which are pills taken by mouth, all of the above therapies are delivered by the intramuscular (IM) route, the subcutaneous (SC) route or the intravenous (IV) route.
Fingolimod is a sphingosine-1-phosphate-receptor modulator that is thought to work by preventing movement of lymphocytes from lymph nodes and in doing so decreases the damage that these lyphocytes can exact on the central nervous system. Cladribine’s mechanism of action is different – 2-chlorodeoxyadenosine triphosphate – an active metabolite of cladribine accumulates in cells, disrupts their metabolism and leads to cell death. Cladribine preferentially impacts lymphocytes and in doing so decreases the number of so called ‘autoagressive’ cells available to attack the nervous system.
The two recently published clinical trials in the New England Journal of Medicine showed efficacy for cladribine (CLARITY trial) and fingolimod (FREEDOMS trial) when compared to placebo over a 2-year period. Statistical significance was achieved for the primary endpoint – which was the annualized relapse/recurrence rate in both trials. In fact, the relative risk reduction was reported as an impressive 50%+ reduction in both trials. In a third trial comparing fingolimod to interferon beta 1a, fingolimod was superior.
Those familiar with the Tysabri story are well aware of the importance of safety when considering immune response modifiers in the treatment of multiple sclerosis and the safety profile of cladribine and fingolimod will surely be closely scrutinized going forward. A detailed discussion of the safety of these oral therapies is not possible here however adverse events of note described in these three trials included herpetic infections, solid tissue cancers, macular edema, basal cell carcinoma, melanoma, breast cancer, transient bradycardia, first- and second-degree heart block, and lymphocytopenia. Should approval of either of these agents occur, physicians and patients will need to do the requisite risk/benefit analysis before initiating treatment and FDA mandated post marketing surveillance will likely be critical in addressing any long term safety concerns.
This brings us to the next question – will physicians and patients get the chance? Well, as mentioned in the first paragraph Merck KGaA was issued a ‘refuse to file’ letter for cladribine suggesting anything but imminent approval while Novartis filed its NDA for fingolimod in late January 2010. Interested readers are directed to www.nejm.org to access the three clinical trials referred to above in their entirety as well as an excellent accompanying editorial. Thanks for reading.
We have all been there. A long-awaited announcement concerning a recently completed clinical trial has just been released. Patients, physicians, investors, executives–anyone with a vested interest in the success or failure of a new drug or medical device–scour a company’s press release, trying to make sense of it. Does the treatment work? Does the drug make a difference? Will the device ever be approved?
The questions may be obvious, but the answers–frustratingly–are often not.
When trying to interpret the seemingly elusive language and technical complexities of a clinical trial report, it is all too common for the experience to end in confusion and decision paralysis. Even worse is the potential for important decisions to be made based on a flawed analysis.
It doesn’t have to be this way. You just need the right information, and the right approach–and this is exactly what our team of expert clinical trial analysts has provided for you below. We’ve demystified the process of interpreting clinical trial results for you in an easy-to-follow, 5-step guide. Using our approach, you will improve your analytical skills, and have the clarity and confidence to make better decisions. So, let’s get started!
How to Read and Interpret Clinical Trial Results
Whether the clinical trial results are coming from a company press release, a conference abstract, or a peer-reviewed medical journal, following these 5 steps every time will improve your analysis and interpretation of trial results.
1.Determine the Trial Type: Preclinical or Clinical (Phase 1, 2 or 3)?
Is this a preclinical trial where the intervention is tested in a lab using an animal model, or a clinical trial where the intervention is tested using human participants? Preclinical trials are important in determing whether a drug is safe and potentially effective enough to enter human trials. Preclinical studies are only the first step in a lengthy process that investigators must complete to move towards approval.
If this is a clinical trial, is it a phase 1, phase 2 or phase 3 clinical trial? Each stage of development is designed to show the investigators and the regulator something different.
Phase 1 clinical trials use a very small number of participants and represent the first use of the drug in humans. Participants may be healthy volunteers or patients with an incurable condition. The focus of phase 1 trials is demonstration of safety, determination of dose range that can be safely administered, and to gain an understanding of how the new drug is metabolized in humans. Phase 1 trials do not tell us about the effectiveness of the new drug.
Phase 2 clinical trials involve a somewhat larger number of patients with the condition the drug is targeting for the purposes of determining the relative efficacy of different doses and frequencies of administration as well as providing more safety data. If the drug appears to work and has acceptable toxicity, investigators will begin the much larger and more expensive phase 3 clinical trial.
Phase 3 clinical trials (sometimes referred to as ‘pivotal clinical trials’) are designed to compare the new drug with an existing drug known to be effective. They involve hundreds if not thousands of patients randomly divided into ‘treatment’ (patients get the new drug) or ‘control’ (patients get an existing effective drug). Most phase 3 trials are randomized and controlled, hence the term Randomized Controlled Trials or RCTS. In most cases new drugs must be shown to be as safe and effective (if not more so than existing therapies) in a phase 3 clinical trial before approval is obtained.
2. If the clinical trial is phase 3, make sure it is a randomized, double blinded, controlled trial.
Most phase 1 and 2 trials are not RCTS. Randomization (random assignment of trial participants to treatment or control), double blinding (investigators and patients don’t know whether they got treatment or not), and controlled (one group gets treatment as is compared to a second group which did not) are the foundations on which the RCT is built. They are critical for the demonstration of a drug’s effectiveness and the prevention or mitigation of the clinical trials worst enemy–bias.
Think of bias as a tendency of a measurement to deviate in one direction from the true value; when it is allowed to run rampant through a clinical trial, it can obscure true beneficial effects of a drug, or worse–hide harmful ones. There may be some very limited medical interventions where double blinding is not possible (surgical interventions, for example). However, checking a trial for randomization, blinding, and a control group is quick, easy andvery important. It should be one of the first things you do in your analysis in order to ensure that the investigators have taken all possible steps to minimize bias and to give you the highest degree of confidence in the trial’s findings.
3. Describe the primary endpoint or outcome of the trial.
The primary endpoint is the main outcome of interest that the investigators were trying to measure. It’s the trial’s “ reason for being”, so to speak. It might be survival in a cancer trial, blood pressure change in a anti-hypertensive drug trial, blood glucose in an oral hypoglycemic trial etc. etc. If you can’t determine the primary endpoint from your information source, you need to dig deeper–most likely you’ll need to find an additional information source (for example, the company website, clinicaltrials.gov, etc.)
Ever wonder why a positive sounding news release is met with an unexpected negative reaction (by investors, for example)? It’s often because the primary endpoint was not met; that is, the treatment effect that the investigators were hoping to measure was not found.
4. Determine if statistical significance was achieved for the primary endpoint.
If statistical significance* was achieved for the primary endpoint, it’s usually stated explicitly by the sponsor if it’s a press release, or included in the results section of an abstract or peer reviewed article. It’s pretty safe to say that if it is not stated explicitly, it didn’t happen!
Be careful of language like ‘results in the treatment group trended towards significance’, or ‘the treatment group improved’ with no reference to statistical testing. Regulators and physicians like treatments that produce statistically significant improvements in primary endpoints, enough said.
*Statistical significance: the probability that an observed outcome of an experiment or trial is not due to chance alone.
5. Look for evidence of poor trial quality.
Before clinical trials are started, all aspects of the trial must be laid out in painstaking detail in the trial protocol. The number and type of patient to be include in the trial, the precise treatment they will be given, the frequency and type of medical follow-up to be received by each participant, even the statistical test that will be used to analyse the results are all examples of the details included in a clinical trial protocol. Once the clinical trial is underway, the protocol should not change. If the protocol changes, be very, very leery of the conclusions reached. Protocol changes will often be difficult to detect so close attention must be paid to company news releases, etc.
Next, look for a description of participant withdrawals in both the treatment and control groups. Withdrawals occur in all trials to some degree; however, large numbers of drop-outs in a treatment group with no explanation is always cause for concern and should serve as a flag to proceed with caution!
So, there you have it. 5 steps we would like you to take every time you read a report of a clinical trial:
1. Determine the trial type
2. If a phase 3 trial – make sure the trial is randomized, double blinded and controlled
3. Describe the primary endpoint or outcome
4. Determine if the drug produced a statistically significant improvement in the primary outcome
5. Look for evidence of poor trial quality
Following the steps above will enable you to more accurately interpret clinical trial results. This will allow you to make better, more informed decisions.
With an FDA decision pending on Mannkind Corporation’s AFREZZA (TM) (insulin human (rDNA origin) Inhalation Powder – formerly named AFRESA ) and the recent failure of the first inhaled insulin to receive FDA approval, we thought it would be helpful to provide an analytical approach to this emerging health technology.
For those who are unfamiliar with the Exubera story, Pfizer received approval for Exubera(R)(insulin human (rDNA origin) Inhalation Powder) in January 2006. As the first approved alternative to injectable insulin, many thought this would represent a milestone in diabetes care destined to take a prominent place in the diabetes therapeutic armamentarium. Things did not turn out this way at all. In October of 2007 Pfizer announced that it was ending production, citing Exubera’s failure to gain acceptance with physicians and patients.
It would be easy to dismiss any inhaled insulin product in the wake of a failure of this magnitude (apparently Pfizer took a 2.8 billion dollar charge as a result of the discontinued Exubera progam). However, developing a sound analytical approach to AFREZZA(TM) should be very informative and allow for an objective assessment of its chances for success.
At BioHorizon, we are emerging health technology-focused. What follows is a list of questions that we have put together that could help to inform your analytical approach to this drug:
1. Does AFREZZA represent true innovation? Is it a first in class therapy, a me-too drug, or something in between?
2. Does it work? In this case we are talking about glycemic control – do patients who take AFREZZA experience better, worse, or similar control of their blood glucose compared to insulin injection?
3. What is the epidemiology of diabetes? In other words, how many new cases, and how many exisiting cases are there in North America? This helps us to understand demand for diabetes treatment. What about the clinical epidemiology? The clinical epidemiology sheds light on how diabetics are treated and tells us about outcomes. This information helps us to establish whether or not there is an unmet medical need and gives us an idea as to where would AFREZZA fit in diabetes treatment protocols.
We ask these three very important questions because we believe that innovative drugs that meet unmet medical needs for highly prevalent conditions change the practice of medicine for the diseases they target. So-called ‘copycat’ therapies that offer incremental or no benefit seldom have the same impact. Answering these questions will give you much needed insight into where AFREZZA sits along this spectrum.
There are two other questions that come to light specifically after examining the Exubera(R) experience.
4. Will patients be required to commit to ongoing pulmonary (lung) function tests once AFREZZA therapy is started? This was the case with Exubera and is felt by some to have been a disincentive to both patients and physicians.
5. Will cost, dosing and inhaler use be acceptable to insurers, patients and physicians? Cost and coverage questions dominate the discussion around medical innovation in this day and age, so having some sense of where insurers stand concerning AFREZZA is important. With Exubera the inhaler was considered large and cumbersome by certain standards and patient and physician feedback indicated that dosing may have been too complicated. Cost, ease of administration and simplicity of dosing changes are important to diabetic patients and physicians contemplating a change in insulin regimens. Do not underestimate these factors in your analysis.
Of course some of these questions will remain unanswered, but we believe that the use of this approach will allow you to establish some important objective parameters and in doing so, help you make better decisions concerning this emerging health technology.
Let us know what you think, and how this approach helped or didn’t help your analysis. Thanks.
There has certainly been a lot of attention paid to ADVENTRX Pharmaceuticals over the past few days so it comes as no surprise that we have had a lot of questions concerning this company’s use of a 505(b)(2) New Drug Application (NDA) for ANX-530. This NDA is different from a full NDA (the usual for a new drug) and different from an ANDA (which is used for generic drugs). The FDA defines a 505(b)(2) application as: “…one for which one or more of the investigations relied upon by the applicant for approval were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted”. It basically allows a company (like ADVENTRX) to ask the FDA for approval of its proprietary formulation of vinorelbine (ANX-530 – vinorelbine emulsion) based partly on safety and effectiveness data generated in the approval of a reference drug, which in this case is Navelbine® (vinorelbine). In its January 10, 2010 press release ADVENTRX states that it is seeking approval for the same indications as Navelbine® including non-small cell lung cancer. The company states that the 505(b)(2) NDA submission includes data from one clinical bioequivalence study designed to assess the pharmacokinetic equivalence of ANX-530 and Navelbine®, the reference drug. As such, the position of ADVENTRX would be that the data required by the FDA for approval can be adequately obtained through a small clinical trial (30 patients or so) relatively quickly and inexpensively compared to the phase I, phase II and phase III clinical trials required to support a full NDA. ADVENTRX believes that by delivering intravenous vinorelbine as an emulsion, ANX-530 can reduce the incidence and severity of vein irritation that may be associated with the administration of this chemotherapeutic agent.
In follow up to our discussion of pneumococcal conjugate vaccines yesterday, we thought readers would benefit from a brief review of the diseases that these vaccines are designed to prevent.
Streptococcus pneumoniae causes acute bacterial infections. Also referred to as the pneumococcus bacteria, it was first isolated by Pasteur in 1881. Prior to the introduction of Prevnar, this bacteria was the most common cause of invasive bacterial infections and acute otitis media (middle ear infections) in North America. Sinusitis, pneumonia, and conjunctivitis are all commonly caused by S. pneumoniae and it remains one of the two most common causes of bacterial meningitis in infants and young children.
Invasive pneumococcal disease (IPD) is defined as the isolation of S. pneumonieae from a normally sterile site (CSF, blood, joint fluid, etc.). For example, bacteremia and meningitis are examples of IPD while otitis media and conjunctivitis are not.
Pneumococci commonly colonize the upper respiratory tract of adults and children. Bacteria are spread person to person by contact with respiratory droplets. Within one month of acquiring the bacteria in the upper respiratory tract about 15% of children will develop disease. Infections are more common in winter months and certain populations are at higher risk including infants, young children, the elderly, black, Alaskan Native and some American Indian populations. Individuals with congenital or acquired immunodeficiency, absent or diminished splenic function, cochlear implants, and a number of other chronic conditions are at increased risk of disease as well. Since Prevnar’s introduction in the United States in 2000 the incidence of all invasive pneumococcal infections has decreased by 80% in children less than 2 years of age, and by 90% for those serotypes included in Prevnar. Corresponding decreases have also occurred in older children and adults as well, possibly due to the interruption of transmission from infants and young children to these older contacts. It should be noted that an increase in incidence of disease caused by serotypes not contained in Prevnar has occurred in some areas.
This overview of clinical presentations and epidemiology is helpful background to those trying to understand the potential impact of a new generation of pneumococcal vaccines, however, greater detail is required to compare and contrast the vaccines of interest. Make sure to visit us again as we explore the unique characteristics of these vaccines in greater detail and thanks for tuning in to the BioHorizon.
Today Biohorizon will take its first look at two new vaccines that promise to make the prevention of pneumococcal disease far more interesting and complex. Both Wyeth and GSK have advanced emerging pneumococcal conjugate vaccine candidates to the filing stage in either the United States, European Union or both. In an effort to understand and scope out some of the questions and controversies surrounding these biologics we need to review a little bit of history…
Since its approval in the United States in 2000 Wyeth’s Prevnar vaccine against pneumococcal disease has helped to transform what was thought of as a mature, marginally profitable segment of the pharmaceutical business into a much more dynamic and profitable one. Prevnar has proven to be both effective and innovative while filling an unmet need in the prevention of serious pediatric infections caused by the pneumococcal bacteria. According to CNN Money.com, Prevnar sales surged 24% in 2007 to $2.4 billion, making it the first vaccine to exceed $2 billion in annual sales.
Prevnar has been the only conjugate pneumococcal vaccine available to immunization programs and clinicians throughout North America and European Union looking to prevent pneumococcal disease. However, GSK’s new 10-valent conjugate pneumococcal vaccine (Synflorix) could soon start changing this.
There are two significant differences between Synflorix and Prevnar that our readers should be aware of. First, Prevnar contains antigen from seven different serotypes of pneumococcal bacteria while Synflorix contains antigen from ten different types. The second difference is in the carrier protein that these polysaccharide antigens are attached to. In Prevnar the protein is called CRM-197 and it has been critical in the success of Wyeth’s product. The carrier protein is more than a passive molecule, it greatly enhances the immunogenicity of the vaccine and makes it more effective. In Synflorix, the carrier protein (NTHi) not only does this, but because it is derived from non-typable Haemophilus Influenza bacteria, provides protection against infections with this pathogen as well. GSK has filed for Synflorix approval in the EU and the vaccine has recently been approved for sale in Canada but we have no word on when or even if approval will be sought in the United States.
The story does not end here as Wyeth is countering with an enhanced version of Prevnar that contains protection against thirteen different serotypes of the pneumococcal bacteria and has filed for approval in both the United States and the European Union.
There are some fundamental questions that need to be explored further concerning the safety and effectiveness of these new vaccines, the changing epidemiology of pneumococcal disease, and of course the cost-effectiveness data that is all important to vaccine program planners. Readers should stay tuned as we plan to explore these crtical areas in the coming days. Thanks for joining us today on the BioHorizon.