NHS England Overhauls Access to Cancer Treatments

Posted by Tom Penrice on Thu,Jun 30, 2016 @ 06:00 PM

Faster cancer treatment access may result from England's reincarnated Cancer Drugs Fund.Patients in England could have faster access to effective cancer treatments through the reincarnated Cancer Drugs Fund (CDF), the National Institute for Health and Care Excellence (NICE) has announced.

The new fund will replace the existing – and greatly overspent – service, which provides access to cancer drugs that are not routinely available at the National Health Service (NHS) in England. Its costs rose to £340 million between 2015 and 2016, following an annual budget of £200 million when it was set up in 2011.

Devised to counter this overspending, the new system will launch in July, fixing the fund's annual budget at £340 million.

Old CDF Versus New CDF

While the existing CDF can choose to pay for innovative drugs that NICE has rejected for widespread use on the NHS, under the new system the health watchdog will make all the decisions.

In a European first, NICE will issue draft guidance on new cancer drugs or significant new license indications before they have received marketing approval in the UK.

Any drug that receives a positive draft recommendation will be funded from the point of license, with NICE normally issuing final guidance within 90 days of the license. Drugs given a “maybe” rating will be considered for the CDF.

The aim is to bring clarity to decisions about which new cancer drugs will receive NHS funding, as well as to allow the NHS to offer conditional funding for those with uncertain evidence for use.

Sir Andrew Dillon, NICE chief executive, commented in a press release: “Patients in this country will now have access to clinically and cost effective, innovative new cancer drugs faster than ever before.”

He added: “In a first of its kind approach, NICE will issue draft recommendations on the use of cancer medicines before they receive their license, with funding from NHS England available if approved. No other country in Europe does this.”

Impact on the pharma industry

If the case for routine use of a drug is not clear cut and more evidence is needed to prove its cost effectiveness, NICE can recommend the drug for temporary, conditional use in the new CDF.

The drug will remain available in the CDF for up to two years while the manufacturer gathers evidence to show that the medicine works and is fairly priced.

After two years, NICE will conduct a review to consider the drug for routine commissioning on NHS England, with the medicine moving out of the CDF and into routine budgets, or being made available on an exception only basis. 

Dillon argued: “The new CDF will be fair. Companies will be given the opportunity to demonstrate their drugs will benefit patients and bring value to the NHS.”

However, concerns about the new fund have been raised, with claims that NICE’s appraisal process could block access to drugs. The Pharma Times reported that the Association of the British Pharmaceutical Industry was disappointed by NHS England’s decision to push ahead with proposals that carry a “very real risk of significantly setting back patient access to cancer medicines, now and for the foreseeable future”.

Paul Catchpole, value and access director of the Association, told the journal: “If cancer medicines go through more or less exactly the same NICE appraisal process that was in place five years ago - which necessitated the setting up of the CDF in the first place - we will largely get the same answers as before - the majority of medicines will be turned down”.

He warned that under the proposals, two thirds of existing CDF medicines would be likely to no longer be available to NHS patients by the end of the year.

Cancer charities agree. In a letter to the British prime minister published in newspaper The Daily Telegraph, 15 charities wrote that many drugs available the western world would "now struggle to gain approval" in England due to NICE’s “last-century methodology”.

The letter stated: "Unfortunately the new system does not update the methodology used by NICE, introduced back in 1999, and many clinically-effective treatments will now struggle to gain approval.”

The charities highlighted that since 2011, when it was launched, the CDF has paid for 84,000 cancer treatments that NICE turned down. Speaking to the BBC, Baroness Delyth Morgan, chief executive of charity Breast Cancer Now, commented: "Not a single breast cancer drug has been considered cost-effective by NICE in the last seven years and this simply cannot continue." Among the breast cancer drugs NICE has rejected is Kadcyla, a treatment which can prolong a dying patient’s life by six months on average.

Cancer Research UK explains on its website that NICE’s approval process is based on whether a drug works, whether it is cost effective and contributions from patient organizations, health professionals and experts.

Important Dates

The current CDF closed on 1 April 2016. Drugs transferring from the old CDF will be appraised by NICE over the next 18 months. Entirely new drugs will be able to enter the CDF from July 2016.

All drugs on the existing CDF list will continue to receive funding until the point that NICE has completed a new appraisal of them, and any patients currently receiving them will finish their treatment.

The CDF was established in 2011 and covers England.

This article is a synopsis of: Faster access to effective cancer treatments through new Cancer Drugs Fund, Cancer Drugs Fund changes deeply concerning, say charities, and What is NICE and how does it work?

Pennside Partners Expands European Presence through new UK office located South of Manchester

UK-Headquarters-Pharma-Biotech-Consulting-Firm-B650.jpgThe Pennside team is excited to announce their new office in Alderley Edge in the UK, 25 KM south of Manchester. This ideal location will help us better serve our European client base due to its proximity to local pharma and biotech companies. Thomas Penrice, Vice President and Partner will be the EU Managing Director. Learn more


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Cancer Drug Development, Cancer

New Cancer Drugs Fuel Debate over Drug Testing Process

Posted by Judi Space on Thu,Oct 17, 2013 @ 06:00 PM

Question:
If the results of initial testing on a drug are amazing – and could mean the difference between life and death – should pharmaceutical companies be required to go through the current long and costly process of drug testing before making it available to the public? 

Is the FDA's quick drug approval process better, or is NICE's cost/benefit approach the right way to go? Read and decide.If a drug is fine-tuned to treat a specific genetic profile, does it make sense to do randomized controlled trials, even if it means delaying the availability of the drug and possibly increasing the cost, thereby rendering it unattainable to certain patients?  

The Renewed Debate over Drug Testing

Two drugs that were recently approved by the United States Food and Drug Administration (FDA) have helped renew this debate. In 2011, Zelboraf, a drug that targets specific mutations in cancer cells, was approved by the FDA after an early-stage trial showed eight out of ten patients experienced significant tumor shrinkage.  Earlier this year, another drug – Tafinlar, a drug targeting the same mutant genes as Zelboraf - was approved by the FDA based on a single clinical trial of just 250 patients. 

Tafinlar is available at 30 percent less the cost of Zelboraf. 

Are Randomized Controlled Trials Becoming Obsolete?

For many years, randomized controlled trials have been the most effective way of seeing if a drug works.  However, according to Richard Pazdur, M.D., the FDA expert who wanted to shorten the Zelboraf trial, “The types of drugs that we’re seeing now are different.  They are just simply better in terms of efficacy.”    Scientists have a better understanding of molecular changes that promote cancer growth.  For example, an estimated 50-60 percent of melanoma patients - the people Zelboraf and Tafinlar target - have a specific genetic mutation. For drugs that focus on patients with specific genetic mutations, randomized controlled trials may not make sense anymore.

Will Faster Drug Approval Impact Pricing?

Eleven of the twelve cancer drugs launched in the United States last year cost more than $100,000 a year per patient.  In April, more than 100 leukemia specialists from around the world spoke up in the American Society of Hematology’s journal Blood that cancer drug prices were “too high, unsustainable, may compromise access of needy patents to highly effective therapy, and are harmful to the sustainability of our national healthcare systems.”

Accounting for 36 percent of the total research expenditure in 2012, clinical trials are the biggest single cost in drug company R&D.  Many contend that if researchers were permitted to test certain treatments on just people with a specific targeted mutation, researchers could work more quickly, and with fewer patients, to determine if the treatment is effective - bringing these treatments to patients more quickly and, possibly, more cheaply.  Unfortunately, there has not been a significant decrease in medications with the most recent changes in testing procedures.  Paul Workman, head of drug discovery for Britain’s Institute of Cancer Research says, “The costs should be coming down tremendously.  What’s disappointing is that we haven’t seen it happen yet.”

European Drug Regulators Vs. FDA

Part of the issue is that European drug regulators and particularly government funding agencies, such as the National Institute for Health and Clincial Excellence (NICE), may not be willing to accept products based on the FDA’s more flexible clinical trial standards.  In Europe, even if a drug is approved by the European regulatory agencies, if the governments don’t approve funding for it, it will still not be available to many people.

It will be interesting to see what happens.  As Workman said, “We are in a fascinating but frustrating period of transition.”

This post is based on Insight: How new cancer drugs can skip randomized trials by Julie Steenhuysen and Ben Hirschler published in Reuters on September 26, 2013.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: FDA, Cancer Drug Development, Drug Development, NICE, Clinical Drug Trials

Heads up for the European Cancer Congress in Amsterdam

Posted by Judi Space on Tue,Sep 24, 2013 @ 06:00 PM

ESMO EU Cancer Congress 2013

Clinical Trial Insights

The annual European meeting offers insights into new data from ongoing clinical trials as well as a chance to discuss the implications of recently reported trial outcomes presented a few short months ago at ASCO. Pennside has reviewed the program in detail and we offer our assessment of key presentations at the meeting for drug developers and biotech.

 

Our Assessment of ESMO Key Presentations:

CRC

  • Analysis of KRAS/NRAS and BRAF mutations in FIRE-3:A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for WT KRAS (exon 2) mCRC (abst#17, embargoed)
    • Data at ASCO this past June showed that there was no benefit from Vectibix for patients with NRAS mutations—it will be interesting to see if this also holds true for Erbitux in this biomarker analysis from the FIRE-3 trial.
       
  • ASPECCT: a randomized, multicenter, open-label, phase 3 study of panitumumab (pmab) vs cetuximab (cmab) for previously treated WT KRAS mCRC (abst#18, embargoed)
    • This is a head to head trial of Vectibix vs. Erbitux in the 3rd line setting—maybe one agent will come out ahead of the other, but most likely they will report similar data, possibly with some differences in safety.
       
  • Effects of regorafenib therapy on health-related quality of life in patients with metastatic colorectal cancer in the phase III CORRECT study (abst#2156)
    • TKIs have a history of poor tolerability in CRC, and Stivarga in particular was concerning because of its use in the 3/4th line palliative setting. However, this analysis appears to show that Stivarga is not detrimental to QOL, and any AEs are manageable with dose modifications.

  • Aflibercept in combination with FOLFIRI for the second-line treatment of patients with metastatic colorectal cancer: Interim safety data from the global Aflibercept Safety and Quality-of-Life Program (ASQoP and AFEQT studies) (abst#2276)
    • There is growing concern within the CRC community that while Zaltrap’s efficacy is similar to Avastin in 2nd line CRC, the tolerability is poor. The data from this study suggests that Zaltrap’s AEs are manageable and may even be lower in the real-world setting vs. the VELOUR trial. 

NSCLC

  • A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer (NSCLC). (LBA2, embargoed)
    • Given the recent vaccine trial failure by GSK in melanoma, we eagerly await the results of the STOP trial for belagenpumatucel-L (aka Lucanix).
       
  • Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): Additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). (3408, embargoed)
    • Key question for followers of PD-1/PD-L1: is there an efficacy/safety differences between inhibiting either target? If not – then it is a race to “first to market”
       
  • Prognostic and predictive role of kras mutations in patients with advanced non small cell lung cancer treated with docetaxel or erlotinib as second line treatment in the TAILOR trial. (LBA32, embargoed)
    • Anything new to learn regarding Kras status in NSCLC? What does a positive Kras status mean for ~20%+ of patients with adenocarcinoma? Hopefully the data will shed new light on this area rather than just casting an intriguing shadow of continued confusion for those who follow NSCLC.

BrCa

  • T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs. treatment of physician's choice (15, embargoed)
    • The TH3RESA trial may provide rationale for the use of Kadcyla in the 3rd line setting for patients who have progressed on Herceptin and Tykerb.  This trial could provide Roche with even more of a stronghold on the HER2+ disease state.
       
  • PARP inhibition with BMN 673 in ovarian and breast cancer patients with deleterious mutations of BRCA1 and BRCA2 (29, embargoed)
    • This data release will provide evidence of the potency of next generation PARPs and will, if successful provide quicker enrollment in the Phase III trial. 

PnCa

  • Additional data from the MPACT trial of Abraxane + gemcitabine vs. gemcitabine in metastatic PnCa (PET response, 2577; peripheral neuropathy, 2583; dosing, 2586)
    • Abraxane was recently approved in the US for the treatment of pancreatic cancer. These three studies will give us more information on response, side effects, and dosing.
       
  • GVAX/CRS207 (2590)
    • This is a new immunotherapy approach for the treatment of pancreatic cancer.  The Ph II study was stopped early due to positive OS results for the combination of GVAX/CRS207 vs. GVAX alone.

Melanoma

  • As it was at ASCO, Melanoma and immunotherapy will be on the hot seat again at this meeting with key presentations in the opening session: Mobilizing the Immune System to Treat Cancer (S, Topalian)
    • With hundreds of mutations extant in patients with advanced cancer, the only way to address the disease is systemically. Immunotherapies are an excellent approach, and research is bearing fruit.
       
  • Vemurafenib and MEK inhibitor, cobimetinib , in advanced BRAFV600-mutated melanoma : Dose-escalation and expansion results of a phase IB study (3703)
    • This MEK/BRAF combination is a very fast follower  of the recently approved GSK agents trametinib and dabrafenib.  Although the two GSK drugs were approved separately, data from ASCO suggests that the combo is better, and KOLs seem to agree that this will become the new standard of care. The two drugs in this study are from Roche who aims to take market share from GSK as quickly as they can. 

HCC

  • Sorafenib alone versus Sorafenib combined with Gemcitabine and Oxaliplatin (GEMOX) in the first-line treatment of advanced hepatocellular carcinoma: Final analysis of the randomized phase II GoNext trial (a UNICANCER / FFCD / PRODIGE 10 study) (2467)
    • This is an update of the previous positive data that was presented at ASCO 2013 this past June—the regimen of Nexavar and GEMOX chemo appears to be active in this population of first line HCC.
       
  • Efficacy and safety of nintedanib vs sorafenib in Asian patients with advanced hepatocellular carcinoma (HCC): A randomised Phase II trial (2580)
    • This study demonstrated that nintedanib has similar efficacy to Nexavar, but with improved tolerability.  As toxicity is a major issue in HCC due to poor patient condition, any agents with improved safety and at least equal efficacy to standard of care would be a welcome addition to the treatment algorithm.
       
  • Subgroup analysis of prognostic factors for overall survival in the SHELTER trial evaluating resminostat in advanced hepatocellular carcinoma (HCC) - the SHELTER Study Group (2601)
    • Data released earlier this month at ILCA showed the potential for a biomarker to select patients most likely to respond to resminostat, and this analysis of subpopulations from the Ph I/II SHELTER study of resminostat alone or in combination with sorafenib may help further define the ideal patient population for this developmental HDAC inhibitor. In particular, the combination of resminostat and sorafenib shows encouraging activity in second line patients who progressed on prior sorafenib.

ThyCa

  • Progressive, metastatic medullary thyroid cancer: Baseline symptoms and disease characteristics among patients enrolled in the EXAM trial (3154)
    • The results from this analysis of the EXAM trial of cabozantinib in medullary thyroid cancer suggest that, despite the common perception that this is an indolent tumor, many patients that present with radiologic findings of progressive disease actually have high disease burden and related symptoms. This justifies approval of two targeted agents in MTC (cabozantinib and vandetanib), as many patients will inevitably need an efficacious therapy once they reach the point of high disease burden.
       
  • Association between tumor BRAF and RAS mutation status and clinical outcomes in patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) randomized to sorafenib or placebo: Sub-analysis of the phase III DECISION trial (3155)
    • This biomarker analysis of the DECISION explored the effect of RAS and BRAF mutations on benefit from Nexavar. While all patients, regardless of mutational status, appeared to benefit from therapy, those with RAS mutations had lowered PFS, while patients with BRAF mutations had improved PFS. Since all patients benefitted from Nexavar, it is unlikely that these biomarkers would be used to select patients for therapy, but important to know that the benefit exists regardless of mutational status.
       
  • An open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer positive for the BRAF V600 mutation and resistant to radioactive iodine (28, embargoed)
    • There is a lot of excitement surrounding the use of BRAF inhibitors in patients with BRAF V600 mutated thyroid tumors. This late-breaking abstract for vemurafenib will be a first look at the potential promise of these agents in RAI-refractory thyroid cancer. 

GBM

  • Bevacizumab, irinotecan and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-non-methylated glioblastoma patients: Updated results from the randomized multicenter GLARIUS trial (3300)
    • This is an update of the data presented at ASCO 2013 this past June. Again, it appears that Avastin/irinotecan therapy prolong PFS in patients with MGMT non-methlyated GBM, where SOC TMZ therapy is ineffective and an active regimen is needed.
       
  • Efficacy and safety of bevacizumab (Bv) plus standard combination temozolomide (T) and radiotherapy (RT) in newly diagnosed glioblastoma: Final results from AVAglio (3301)
    • An update of the AVAglio data presented at ASCO—final OS data will be presented at the meeting. The additional data coming at ESMO may help clarify the role of Avastin in GBM, where data has been inconsistent. 

STS

  • PICASSO 3: A phase 3 international, randomized, double-blind, placebo-controlled study of doxorubicin (dox) plus palifosfamide (pali) vs. dox plus placebo for patients (pts) in first-line for metastatic soft tissue sarcoma (mSTS) (3802)
    • The failure of the PICASSO trial once again shows the need for more targeted trial designs in Soft Tissue Sarcoma.  KOLs continue to press for better targeted trials in this difficult group of diseases.
       
  • Final results of sequential phase 2 studies of palbociclib
    (PD0332991) in CDK4-amplified liposarcoma  (3826)
    • The use of CDK4 amplification as a biomarker may provide palbociclib with a targeted approach in Sarcoma that will prove effective.  The Phase III trial is being planned. 

NET

  • A randomized, double-blind, placebo-Controlled study of Lanreotide Antiproliferative Response in patients with gastroenteropancreatic  NeuroEndocrine Tumors (CLARINET). (LBA3, embargoed)
    • IPSEN has announced that lanreotide has meet it’s primary endpoint in the CLARINET and ELACT trials.  The presentation on Saturday should give us insights into the robustness of the data and an expectation for ELECT at ASCO GI in January, 2014.  


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Drug Developers, Cancer Drug Development, Drug Development, Breast Cancer Drug Development, Breast Cancer Oncology, ASCO, ESMO

Do We Need Phase III Randomized Controlled Trials for EVERYTHING?

Posted by Judi Space on Thu,Aug 29, 2013 @ 09:00 PM

Targeted therapy agents

Phase 3 randomized controlled trials - time to drop in some cases?In clinical trials of targeted therapy agents, sometimes the target is such a crucial driver of the neoplastic process, that its inhibition is able to stop the growing tumor in its tracks. This appears to be the case for some recently approved agents such as vemurafenib for BRAF V600E melanoma and crizotinib for ALK+ NSCLC. Careful screening of patients for these mutations ensures the likelihood of improved progression free survival (PFS) and longer survival times. Unfortunately, because patients are switched from the control regimen in the Phase III trials, the chances of proving better survival are greatly diminished, if not completely eliminated.

In a recent opinion piece in Nature Reviews: Clinical Oncology, Robert Doebele argues that when patients are screened for the relevant oncogene "the burden of proof for approval should be adjusted for oncogene-targeted therapy in biomarker-selected patients....There might be oncogenes that will not follow this paradigm, but that should not deter us from trying to extend the benefit of this precision medicine approach to patients that may fall into one of these uncommon oncogene categories." 

Crizotinib for ALK+ NSCLC

One example is crizotinib, a tyrosine kinase inhibitor (TKI) for the treatment of ALK gene rearrangement-positive (ALK+) non-small-cell lung cancer (NSCLC), which was approved by the FDA in 2011 based on the results of phase I and phase II clinical trials. Phase I observed an objective response rate (ORR) of 61% and a PFS of 9.7 months.  Phase II observed an ORR of 53% and a PFS of 9.1 months.

Considering the estimated ORR and PFS for most single-agent chemotherapy drugs in pretreated patients with lung cancer is 10% and 3-4 months respectively, was there really a need for a Phase III RCT in this case? 

The outcome of a phase III randomized trial, PROFILE 1007, of crizotinib in patients with ALK+ lung cancer merely provided further proof that cizotinbin is superior to standard chemotherapy for these patients that included a better quality-of-life and physical and emotional function.  Based on the results of this study, it seems reasonable to argue that the burden of proof for approval should be adjusted for oncogene-targeted therapy in biomarker-selected patients, especially in lung cancer. 

Not limited to TKI

Calls for the elimination of Phase III trials are not limited to TKI. During the presentation of a melanoma Phase II trial of a combination of two immunomodulators, ipilimumab and nivolumab at ASCO this year, one of the questions from the audience was, "Do we really need a phase III trial?" The results of the trial being presented were certainly impressive, with one year survival in the 80% range.

Time to shift the burden of proof?

Based on these examples, some feel that it may be time to eliminate the Phase III trial in targeted therapy agents when such overwhelming proof is given that a therapy induces remarkable tumor responses in Phase I and II.  This will allow studies to move along more quickly, minimize the need to switch patients from the control regimen, and provide more rapid approval for certain therapies.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Oncology, Targeted Therapy, Cancer Drug Development, Drug Development

Defining Success in Clinical Trials: Is Learning Something Enough?

Posted by Judi Space on Thu,Jul 25, 2013 @ 06:00 PM

Avastin discussed at ASCOAt last month’s ASCO conference, rapt attention was given to a presentation on the clinical trial results for the drug Avastin for patients recently diagnosed with an aggressive form of brain cancer, glioblastoma multiforme (GBM), according to an article by Clinton Leaf appearing in the New York Times, which is summarized below, with our comments added. The presentation by Dr. Mark R. Gilbert, professor of neuro-oncology at the University of Texas M. D. Anderson Cancer Center, revealed earlier clinical trial results that were encouraging:  tumors shrank and the disease appeared to stall for months in two smaller single-arm studies.

No Difference

However, Dr. Gilbert’s larger double blind study of over 600 brain cancer patients found no difference in the survival rate for patients given a placebo with standard treatment vs. those given Avastin with standard treatment.  In effect, the larger, more reliable double blind study eliminated doubt as to the general effectiveness of the drug.   In other words, the trial was “a success” because it had a clear result, but we learned that the drug has no statistically significant impact on the disease as a whole. But is that enough for the trial to truly be deemed a success?

It depends on how you define success. On one hand, doctors have no additional information on how to successfully treat brain cancer as a result of the study. On the other, one possible solution has been eliminated, so doctors and pharmaceutical companies can continue their quest for an effective drug armed with the knowledge from the study.

Not so Fast

The problem is that it is not quite as cut and dried as all that. Some patients who take Avastin do significantly better than those who do not. However, the trial failed to reveal the responders that make this result possible. Despite 400 clinical trials over 16 years, no correlation has been made as to why Avastin works or fails to work in certain patients. Again, given that we don’t know, can we deem the trial a success?  

Individualized Factors May Hold the Key

Researchers are learning that individualized pathology and physiology may be significant factors in developing effective drugs for treating certain diseases.  The variability of tumors and cancers at the genetic level can be great, as can the way our genes affect our response to drugs. So the solution to some diseases may lie in identifying the drugs that best align with the individualized factors associated with a given disease.

Failure rates in clinical trials tend to increase significantly as the drug moves from phase I to phase II. In the final phase it is not unusual for trials to wholly contradict earlier trials, or for the benefits to be far less than what was first reported, according to a 2005 paper published in the Journal of the American Medical Association by Dr. Ioannidis, an authority on statistical analysis.

The Difficulty of Matching Clinical Trial Populations to Patients

Rules governing statistical trial enrollment typically produce trial populations of younger and healthier members than those likely to use the drug. In addition, trial populations typically have had far less medical treatment. These factors combine to form somewhat of a mismatch between the trial population and patients. Given that the vast majority of drugs that enter clinical testing fail to get approved (95%), finding ways to match clinical trial participants with the appropriate genetic or molecular signature may be paramount to finding drugs that work.  

That’s the approach taken by Genentech in developing Herceptin, a breast cancer drug that targets tumor cells with an abundance of the HER2 protein. Small clinical trials were designed that enrolled only those with the required molecular or genetic signature. 60% of the new drugs in development at Genentech/Roche are being developed in concert with a diagnostic test to determine patients most likely to benefit. They did not go that route when they developed Avastin and tested it in patients with GBM.

Back to the Question at Hand

So, is it enough to simply learn something from a clinical trial, even if we don’t find a solution to treat a disease? Given that there is so much riding on finding drugs that improve and extend the lives of those suffering, anything that moves us forward, even if only eliminating what was thought to be a potential solution, is a step in the right direction.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: FDA, Oncology, Targeted Therapy, Cancer Drug Development, Oncology Clinical Trial Design, Breast Cancer, Breast Cancer Drug Development, Breast Cancer Oncology, Glioblastoma, ASCO

Breakthrough Therapy Opens Door to Streamlined Drug Development

Posted by Rebecca Levine on Wed,May 15, 2013 @ 07:51 AM

The FDA's New Breakthrough Therapy Designation

What does the FDA's new Breakthrough Therapy designation mean for pharma and biotech firms? Commentary by Pennside Partners, consultants to the pharmaceutical and biotechnology industries.The FDA recently added a new designation, ‘Breakthrough Therapy’, to its roster of pharmaceutical regulatory terminology in order to ensure that truly innovative compounds get to the patients who need them most as soon as possible.  This new designation was enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA).  The Breakthrough Therapy designation will provide companies with the opportunity for a streamlined developmental process, which could greatly shorten the development timeline. 

How the Breakthrough Therapy Request Process Works

A company can request the designation from the FDA at any time after the original IND submission, but is under no obligation to publicly announce the request.  Once the FDA grants the compound the Breakthrough Therapy designation, the process for approval becomes abbreviated.  The FDA representatives effectively form an advisory panel with the company, in order to determine the most efficient trial designs.  The review time will also be shortened due to the rolling NDA / BLA submission. 

Oncology Likely to Benefit Most

While the language of the bill does not specifically refer to oncology as a primary source of Breakthrough therapies, it is likely that a majority of these designations will apply to oncology compounds.  Other diseases that have already received Breakthrough Therapy status include the rare genetic disease epidermolysis bullosa, hepatitis C and cystic fibrosis. 

Flexible Approval Standards

These new breakthrough therapies must show early clinical evidence of a substantial improvement over existing therapies for serious or life-threatening diseases.  The bill purposefully left the approval standards vague, so that a judgment call can be made by the reviewers at the FDA.  There is no efficacy bar set; however officials warn that if a company wonders if their drug is in a grey area, it is unlikely to be a true breakthrough. 

Rigorous Data Requirements Remain

The data requirements for Breakthrough Therapies will be as rigorous as other submissions, but other faster trial designs may be possible for these compounds.  The options could include a phase Ib expansion or single-arm pivotal trial for diseases states where there is no standard of care.  A phase IIb randomized controlled trial with a modest-sized population might also be an option for some of these compounds where substantial efficacy benefit is seen over the standard of care.  Both these options and others could lead to either full or accelerated approval.

50% Breakthrough Therapy Approval Rate So Far

Over a dozen companies have already sought the Breakthrough Therapy designation, with approvals being granted to approximately half.  One of the compounds recently granted Breakthrough Therapy status is Pfizer’s palbociclib, an oral inhibitor of cyclin-dependent kinases (CDK) 4 and 6.  The designation was granted based on preliminary data from their phase II trial in first-line post-menopausal patients with ER+, HER2- locally advanced or metastatic breast cancer.  Interim data presented at the 2012 San Antonio Breast Cancer Symposium showed that women treated with the combination of palbociclib plus letrozole achieved a statistically significant improvement in median progression free survival (PFS) compared to women who received letrozole alone (26.1 months and 7.5 months, respectively).

Official FDA Guidance Set for July 2013

The official master guidance will be released by the FDA in July of 2013; however it is clear that this new designation will provide a significant benefit to qualifying extraordinary therapies. 

Pharmaceutical Industry Hurdles

What remains unclear at this time is how the already underfunded FDA will manage to provide even more time and attention to these compounds and how much the designation will actually streamline the regulatory pathway. 


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: FDA, Oncology, Cancer Drug Development, Drug Development, Breakthrough Therapy, FDASIA

Heads up for ASCO: Our List of Key Oncology Presentations

Posted by Judi Space on Tue,May 07, 2013 @ 06:00 PM

Expect the biggest data dump of the year at this annual cancer mega-conference

ASCO Oncology and Drug Development Conference Highlights May June 2013

 

 

 

For those of us taking an interest in Biotech and Drug Development the largest release of new clinical data is just around the corner at the annual American Society of Clinical Oncology (ASCO) meeting to be held in Chicago starting on May 31. In ASCO’s preliminary press release, the organization revealed what it thought were the key presentations to be presented at the meeting.  The actual abstracts will be posted on the ASCO website on May 15th, but the titles of the presentations are available now.

Pennside always sends a large team to ASCO to review the data and discuss its implications with experts in the field.  After reviewing the entire program, we have a hit list of what we believe are the most important studies to be presented at the meeting, especially regarding development of targeted therapies for a number of cancer indications.

Breast Cancer:

    • Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3). (Abstract #505)

One of the most important data releases this year at ASCO in Breast Cancer will be the preliminary results from the BOLERO-3 trial of Afinitor in combination with Herceptin and vinorelbine in HER2+ metastatic Breast Cancer patients.  Results were expected at the San Antonio Breast Cancer Symposium in 2012; however there had not been enough events to report at that time.  This trial should clarify whether Afinitor can be used to reverse resistance to HER2 therapies as well as it does with hormonal therapies.  If successful, this will expand the reach of Afinitor into the 2nd line of HER2+ Breast Cancer therapy, where its side effect profile will not cause the hesitance that it has in the ER+ populations.

  • A phase II trial of an oral CDK 4/6 inhibitor, PD0332991, in advanced breast cancer. (Abstract #519)

Interest remains extremely high for the anti-CDK4/6 inhibitor palbociclib from Pfizer.  More data from the Phase II trial will be released during a poster discussion session at ASCO.  The preliminary data seen at SABCS in 2012 was very significant and if these further results support it, the approval of this compound will dramatically affect the 1st line treatment of advanced ER+ Breast Cancer.   Since the FDA granted palbocicllib the designation of Breakthrough Therapy, the oncology community is very focused on how this will affect it’s developmental pathway. 

Colorectal Cancer:

  • Analysis of KRAS/NRAS, BRAF mutations in the phase III PRIME study of panitumumab plus FOLFOX versus FOLFOX as first-line treatment for mCRC (abst# 3511)

ASCO granted an exception to its abstract policy so that data from this analysis could be released early (17 April) because it shows that patients with certain RAS mutations beyond KRAS may have a negative outcome from treatment with Vectibix. ASCO and Amgen strongly believe oncologists need this information now in order to make informed decisions about choosing effective treatments for their patients.

  • Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type mCRC: German AIO study KRK-0306 (FIRE-3) (Abst# LBA3506)

Outcome of this trial may determine if patients truly benefit from this class of drugs in the first line setting.

Non-Small Cell Lung Cancer (NSCLC):

    • A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1) (Abst# CRA8007)

This is Synta’s lead product for 2nd line NSCLC. Previous interim results from GALAXY-1 have been positive, which leads us to suspect that this interim analysis will continue in a positive trend.  Final data (PFS/OS) for GALAXY-1 should be ready in time for EMSO2013 in Amsterdam or WCLC2013 in Sydney. The key for ganetespib’s initial success lies in any additional toxicity in combination with docetaxel. Note that GALAXY-2 (Phase III 2nd line NSCLC with docetaxel) has recently began enrolling patients. Clinicians will clearly contrast ganetespib with nintedanib (see below).

    • Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after first-line chemotherapy: LUME Lung 1, a randomized, double-blind phase III trial. (Abst# LBA8011)

This is Boehringer Ingelheim’s second foray into the NSCLC. Their lead agent, afatinib is currently under regulatory review with both the FDA and EMA. Like ganetespib above, the key issue for nintedanib is toxicity in combination with docetaxel (provided the data is positive).Nintedanib clearly has the early lead when compared to ganetespib for becoming the newest agent in 2nd line NSCLC. Positive data in  LUME Lung-1 would be the second shot in the goal for Boehringer Ingelheim and their NSCLC franchise.

Prostate Cancer (PrCa):

  • Abstract #5016: A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results (Abst# 5016)

With the increasing number of approved treatments available for prostate cancer the biggest challenge is how to best sequence the drugs to maximize efficacy and minimize toxicity.  Because Provenge does not alter PFS but does improve survival, there has been much discussion regarding the optimal place for its use.  This abstract may offer some guidance or at least improve understanding.

 

    • Abstract #5004: ERG rearrangements and association with clinical outcome in patients (pts) receiving abiraterone acetate (AA) (Abst#5016)

Results from the COU-AA-302 study in chemotherapy (chemo)-naïve metastatic castration-resistant prostate cancer (mCRPC): The increasing number of targeted cancer therapies in development has necessitated the need for biomarkers to aid in determining patients most likely to respond to and benefit from each treatment.  Biomarkers will be increasingly valuable for patients and physicians in the decision making process.   ERG rearrangement in prostate cancer at the time of diagnosis, are markers for predicting subsequent tumor behavior and can help in better predicting the clinical outcome.

Kidney Cancer (RCC):

    • Record-3: Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in mRCC (abst# 4504)

Trials evaluating sequencing of targeted therapies are always important in RCC, although mTOR use is uncommon in the first line setting. 

    • Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in mRCC (Abst# 4505)

This is early data, but it will be interesting to see how this agent compares to BMS’ nivolumab (anti-PD1), which is already in Ph III for RCC.

Melanoma:

    • Long-term follow-up data on the safety and efficacy of singe-agent nivolumab (an anti-PD-1 antibody) in patients with advanced melanoma (Abstract #CRA9006)

Nivolumab (BMS) , a new immunomodulator, made a big splash at last year’s ASCO and BMS has lost no time in fleshing out its development program across a number of tumor types.  Since its debut last year companies with other agents like nivolumab have sprung into action, with clinical data presentations for quite a few of them on the schedule.

    • Findings from a Phase III trial exploring the effect of the anti-PD-L1 antibody drug MPDL3280A in patients with locally advanced or metastatic solid tumors (Abstract #3000)

This study of MPDL3280A (Roche) in patients with solid tumors will be presented by Roy Herbst (Yale). It is most unusual for a Phase III trial to include patients with many different tumor types, and we are intrigued by what Roche plans to do with the data (should the study be positive).

    • BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM). (Abst#9005)

Interest is high here for this combination of TKIs from GSK. Phase II data was very promising at last year’s ASCO, and NDA has been filed with the FDA, so any updates will be followed very closely by all stakeholders.

Glioblastoma (GBM):

    • RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab in newly diagnosed GBM (Abst# 1)

ASCO’s top abstract. Presentation of results from this trial, along with the previously-reported AVAglio trial, will help determine the benefit of adding Avastin to standard chemo and radiotherapy in newly-diagnosed GBM.

    • Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-nonmethylated GBM: First results from the randomized multicenter GLARIUS trial (Abst# LBA2000)

GBM patients with non-methlyated MGMT are resistant to treatment with the current standard of care chemotherapy (temozolomide), so if Avastin/irinotecan proves useful in this setting, it will be an important option for this group of patients who are currently without effective therapy.

Thyroid Cancer (ThyCa):

    • Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The Ph III DECISION trial (Abst# 4)

Another top Abstract at ASCO: Earlier this year, Bayer announced that DECISION met its primary endpoint, so it will be exciting to see just how effective Nexavar is in this difficult setting in thyroid cancer.

    • Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer (6024)

It will be interesting to see if the addition of Afinitor to Nexavar (which is known to be effective in thyroid cancer) will add any additional benefit.

Liver Cancer (HCC):

    • Sorafenib alone versus sorafenib combined with gemcitabine and oxaliplatin (GEMOX) in first-line treatment of advanced HCC: Final analysis of the randomized Ph II GONEXT trial (UNICANCER/FFCD PRODIGE 10 trial) (Abst# 4028)

The GONEXT trial will show if the addition of Nexavar to chemotherapy can improve outcomes in HCC, where chemotherapy alone is not very effective. HCC is a difficult disease, and many patients have difficulty with the side effects of Nexavar alone—this combination will have to overcome the potential for increased toxicity with some significant benefit in survival in order to be successful.

    • Ph II trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, followed by sorafenib in patients with advanced HCC (Abst# 4122)

Oncolytic viruses are a novel approach in oncology, particularly in HCC. This Ph II data will hopefully be the first indication of whether Pexa-Vec will be effective and well-tolerated.


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Oncology, Cancer Drug Development, Drug Development, Breast Cancer, Breast Cancer Drug Development, Breast Cancer Oncology, Kidney Cancer, Liver Cancer, Thyroid Cancer, Glioblastoma, Melanoma, Prostate Cancer, Lung Cancer, Colorectal Cancer, ASCO

NCI Improvements: Drug Development Opportunity for Pharma and Biotech

Posted by Judi Space on Tue,Mar 12, 2013 @ 06:00 PM

Three years ago the Institute of medicine declared that the nation’s cooperative group system for conducting clinical trials was so moribund as to not be an effective vehicle for the generation of scientific data in a timely fashion. In a report generated in 2010, the IOM recommended that the number of cooperative oncology groups be reduced from 10 down to 5[1], improve speed and efficacy of the trial processes as well as incorporate new scientific discovery into clinical protocols. Along with this, the report said it was critical to create a data platform that would assist in the administration of trials across all of the remaining cooperative groups. This would be a system to which both large academic centers and community cancer centers could adhere.

NCI Less of a Barrier; More of a Facilitator

To a large extent, the NCI was  a barrier to the conduct of clinical trials due to their role of providing oversight. The IOM report urged that NCI become part of the solution by helping to prioritize and design trials as well as directing patients to relevant studies so that enrolment could proceed more rapidly. In addition, CMS was tasked with removing barriers to enrollment by supporting appropriate costs associated with patient treatment during the trials.

Efforts Bearing Fruit

Now, nearly three years later, we can see the effects of this report. In a two day workshop[2] that took place in Washington last month, improvements in the national cooperative group trial system were documented[3]. Among the improvements noted:

  • The time between concept and activation of phase II trials sponsored by NCI has shrunk by more than a third. Trials not meeting timelines will be terminated!
  • Time to activation for phase III trials has been halved since the overhaul process began
  • The number of cooperative groups has actually been cut in half – now there are only 5
  • A common enrollment and data management system has been put into place
  • Patients can enroll 24/7 and they may participate in ANY Ph III trial in the system regardless of origin
  • There are now  standardized agreements for industry collaborations
  • A new  review process has been launched for grading the quality of trials
  • Integrated biospecimen banks are being created

Still to come are more innovative Ph II trials based on molecular biology of the tumors and the extensive use of biomarkers and genomic profiling.

Ecology of Clinical Trials

Community Cancer Centers are Key

The key to moving clinical research forward more rapidly will be enhanced participation of community cancer centers. Investigators at these sites are often hesitant to take part as many of the costs associated with the trials are not covered.  After more provisions of the Affordable Care Act go into effect, next January, this may no longer be a barrier. Federal law will require insurers cover the cost of routine patient care in clinical trials.

Design and Conduct of Trials Improving in UK As Well 

Interestingly, the US is not the only place that has had a sea change in the way it conducts clinical research for cancer. Over the same period, the UK’s National Health Service has recognized that clinical research is an important part of its mission, and therefore has provided incentives for patients to participate in trials. The key here is that cancer patients do not get access to novel agents unless they participate in the trials. The result is a trials network that rivals anything in the US but existing in a much smaller country.

 

Implications for Drug Development:

Drug approval process improving in the UK as well as the US

Pharma  and biotech companies can harness the power of the NCI to get things done faster than they have become accustomed to in the past, and the improvements will continue into the foreseeable future. This is also good news for cancer patients who will be able to access more cutting edge clinical trials no matter what part of the country they are from.

 


[1] http://www.iom.edu/~/media/Files/Report%20Files/2010/A-National-Cancer-Clinical-Trials-System-for-the-21st-Century-Reinvigorating-the-NCI-Cooperative/NCI%20Cancer%20Clinical%20Trials%202010%20%20Report%20Brief.pdf

[2] http://www.iom.edu/~/media/Files/Activity%20Files/Disease/NCPF/2013-FEB-11/Agenda%20-%20IOM%20ASCO%20Implementation%20Workshop.pdf

[3] http://www.nap.edu/catalog.php?record_id=18273


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: FDA, Drug Developers, Oncology, Predictive Biomarkers, Targeted Therapy, Data Standardization, NCI, Cancer Drug Development, Oncology Clinical Trial Design

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