Latest Drugwonks' Blog
The Marine Corps Marathon is being run this weekend in Washington, DC. The whole idea of a marathon never made sense to me.. why run that far when we have cars to get you there faster?
But that was before I met Don Wright. Don is 74 and running in his 90th -- as in just 10 less than a 100 -- marathon.
Oh, and Don has had multiple myeloma since 2004.
I met Don about 40 marathons ago in 2012. He had just finished running his 50th marathon in Hawaii, which was the 50th state in which Don has completed such a race.
He was diagnosed with the disease 12 years ago when his doctor told him that he had about 4 years to live, max. Back then, all he wanted to do was run one marathon. He was fortunate enough to be put on an experimental medicine (now approved) that knocked the disease into remission. As he has said more than once (but never enough)" It's just a little.. pill that I take every night." Earlier this year Don was worried that he wouldn't be well enough to run the Marine Corps event. It wasn't cancer. He had a pulled hamstring from overtraining!
I have had the deep privilege of spending time with Don. He is a powerful voice for medical innovation, a loving and dedicated husband and father and a source of comfort and support for everyone reeling from the diagnosis of a deadly disease.
The greater marathon runner Bill Rogers once said, "the marathon can humble you." Don Wright has shown that it can inspire us as well.
The American Academy of Pain Management sent this letter to the chair and key members of the House Energy and Commerce Committee, regarding the flawed process used by CDC in developing its opioid prescribing guidelines. The letter was also sent this letter to the chair and ranking member of the Senate HELP Committee.
The letter details the most important methodological shortcomings in CDC’s process, and asks that the committees investigate to determine why a more robust and appropriate procedure was not followed. Finally, the Academy asks the committees to suggest to CDC that they scrap this guideline and start over, using a more inclusive process.
This issue is not going away.
See what happens when regulation doesn't get in the way of producing valuable technologies?
Let's hope that this important article can be the foundation for a broader effort to promote faster, less expensive access to new medicines.
The Urgent Need for Clinical Research Reform to Permit Faster, Less Expensive Access to New Therapies for Lethal Diseases
October 19, 2015
Written by David J Stewart, Gerald Batist, Hagop M. Kantarjian, Joan Schiller, John-Peter Bradford, Razelle Kurzrock
High costs of complying with drug development regulations slow progress and contribute to high drug prices and, hence, mounting health care costs. If it is exorbitantly expensive to bring new therapies to approval, fewer agents can be developed with available resources, impeding the emergence of urgently needed treatments and escalating prices by limiting competition. Excessive regulation produces numerous speed bumps on the road to drug authorization. Although an explosion of knowledge could fuel rapid advances, progress has been slowed worldwide by inefﬁcient regulatory and clinical research systems that limit access to therapies that prolong life and relieve suffering. We must replace current compliance-centered regulation (appropriate for nonlethal diseases like acne) with “progress-centered regulation” in lethal diseases, where the overarching objective must be rapid, inexpensive development of effective new therapies. We need to (i) reduce expensive, time-consuming preclinical toxicology and pharmacology assessments, which add little value; (ii) revamp the clinical trial approval process to make it fast and efﬁcient; (iii) permit immediate multiple-site trial activation when an eligible patient is identiﬁed (“just-in-time” activation); (iv) reduce the requirement for excessive, low-value documentation; (v) replace this excessive documentation with sensible postmarketing surveillance; (vi) develop pragmatic investigator accreditation; (vii) where it is to the beneﬁt of the patient, permit investigators latitude in deviating from protocols, without requiring approved amendments; (viii) conﬁrm the value of predictive biomarkers before requiring the high costs of IDE/CLIA compliance; and (ix) approve agents based on high phase I–II response rates in deﬁned subpopulations, rather than mandating expensive, time-consuming phase III trials. Clin Cancer Res; 21(20); 4561–8. 2015 AACR.
A recent article by Shashi Amur and FDA colleagues on the future of biomarker development (Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization) provides a solid foundation for ongoing development and review process for biomarker qualification. FDA should be applauded for their progress in agency collaboration with the Critical Path Institute (in biomarker consortia development), the recent total kidney volume and plasma fibrinogen prognostic marker approvals, and sponsorship of interactive sessions such as the recent CERSI meeting at University of Maryland, as well as their EMA partnership to facilitate collaborative review of drug development tool qualification.
We would encourage additional measures to hasten biomarker development, including:
- Maximizing Expert Resources: FDA needs adequate resources to provide advice and oversee review and decision-making. One solution is to partner with an external entity (an Intramural Biomarker Consortium-IBC) to develop early advice and serve as an expert sounding board for nascent biomarker efforts. The IBC could be a required or voluntary resource in the review process, especially for initial data package reviews. This approach would allow FDA staff to focus on their primary role of product review and regulatory oversight.
- Refined Evidentiary Considerations: The product development and research community should collaborate to support FDA in developing a framework for the proper level of evidentiary substantiation required for qualification and the criteria used to evaluate them – such that FDA can issue guidance -standards which do not exist today. The IBC could be charged with overseeing relevant workshops and the drafting of initial guidance documents (consistent with FDA’s Good Guidance Practice recommendations and provided FDA is actively participating and has final approval).
- Qualification Plan: FDA should clarify the components of individual qualification plans and judge submitted data packages against them. Decisions not to qualify a proposed biomarker for a particular context should be accompanied by an explanation of the evidentiary gaps between the agreed plan and the submitted qualification package. IBC could work with biomarker developers to build these plans and perform initial data package reviews.
- Enhance Learning: Give FDA the authority to share information about biomarker qualification programs that are being advanced through collaborative efforts. Much can be learned by reviewing successes and failures across ongoing biomarker programs, and would inform the broader research community to enable refined evidentiary standards.
- Timeliness: FDA must clarify and communicate timelines for the qualification process in order to foster predictability and encourage participation. Such resources could be provided via PDUFA VI.
FDA can further solidify its place squarely in the center of the innovation ecosystem by fostering collaborative alliances with all stakeholders, enhancing qualification planning, sharing developmental endeavors, and clarifying standards.
Peter J. Pitts
President, Center for Medicines in the Public Interest
Former FDA Associate Commissioner
Timothy R. Franson, M.D.
Chief Medical Officer – YourEncore
Immediate Past President- US Pharmacopeial Convention
Moreover, rebates cost biopharma about $40 billion each year. Nearly 90 percent of that $40 billion ($36 billion) is passed on to health plans by PBMs. In 2014, health insurers generated $663 billion in revenue, which means drug rebates are about 5 percent of total revenues.
I now see another layer to the strategy of make drug prices, which are effectively set by PBMs and insurers with higher coinsurance, the issue and blaming drug companies. It's all about making money coming and going. PBMs and insurers can extract deeper discounts from companies whose products they carry AND get the innovator firms to pay for the chunk that consumers have to cover:
Adam discussed an IMS study " Emergence and Impact of Pharmacy Deductibles: Implications for Patients in Commercial Health Plans" As he notes: "The report’s overarching theme is unsurprising: Higher out-of-pocket costs reduce patients’ adherence to drug therapy and increase prescription abandonment rates.
The report’s major contribution, however, links the growth in pharmacy deductibles to manufacturers’ copayment offset programs, which cover a beneficiary’s out-of-pocket costs for a brand-name drug. High deductible plans are shifting costs from payers to consumers and—in many cases—back to manufacturers.
The findings echo what payers have been doing by adding coinsurance rates to higher-tier products, per Employers Get Tougher About Pharmacy Benefits and Specialty Drug Management. Most people can’t afford to pay hundreds or thousands of dollars every month. Payers are therefore essentially daring pharmaceutical manufacturers not to pick up the patient’s coinsurance with a copayment offset program. This is the same dynamic that links the growth in four-tier benefit plans with copay offset program. See How the Fourth Tier Coinsurance Boom Drives Copay Offset Programs.
I’m not sure how many manufacturers have analyzed the codependent relationship between benefit design and their consumer-directed programs. This report suggests that such analysis would be truly therapeutic."
To which I would add.. maybe the innovators should show consumers how their drugs are priced by insurers to force them to cover the difference and suggest how patient hostile such an approach is. This co-dependency undermines the doctor patient relationship and moves medicine away from the kind of personalized treatment selection medical innovation is making possible.
Wither FDA? Also, what about addressing incentives/responsibilities for enhanced physician/pharmacist/patient reporting?
From the pages of FDA News ...
EMA Releases Pharmacovigilance Program Update
Drugmakers must begin using a new centralized database for product safety update reports by mid-2016, the European Medicines Agency says.
The updated repository will also link the PSUR single assessment procedure number with products, making searches easier, and will allow for an automated two-way exchange between national authorities’ IT systems and the PSUR repository.
Use of the repository becomes mandatory on June 13, 2016. Until then, marketing authorization holders must continue to submit PSURs to national competent authorities.
The EMA is also finalizing revisions to its EudraVigilance Access Policy, which would give drugmakers greater access to adverse event reports, beginning in mid-2017. The agency’s management board is set to vote on the policy in December.
The EudraVigilance website will be updated in November with the publication of key documents such as the Stakeholder Change Management Plan, which details the IT and business changes companies need to make before reporting begins, the EMA says.
The EMA also plans to release a report this month on the launch of its Medical Literature Monitoring initiative, which allows drugmakers to easily search for information on adverse reactions associated with their products.
In addition, the EMA has launched an online invoice portal where companies can pay their annual pharmacovigilance fees. Under the fee program, which took effect in July, drugmakers must pay $70 for each product they market in the EU.
The agency has also updated its database of 500,000-plus drug products and is giving member states access to it. Drugmakers should enhance their in-house systems to allow for receipt of acknowledgment messages regarding new and modified marketing authorizations, beginning Nov. 4.The changes were mandated in the 2012 pharmacovigilance legislation. View the EMA’s Pharmacovigilance Program Update at www.fdanews.com/10-14-15-PharmacovigilanceProgrameUpdate.pdf.
NCCN, like the American Society for Clinical Oncology (ASCO) has create a framework telling doctors and patients that in selecting treatments some medicines are worth more than others.
NCCN, like ASCO, claims choosing which medicines are most affordable will address “the combination of increasingly unsustainable rises in the costs of cancer care, the accelerating pace of expensive innovations in oncology, and persistent hope for rescue in patients with life-threatening disease.” Apparently, persistent hope is something we should discourage because saving a few dollars is more important.
However, the assertion that cancer costs are unsustainable is untrue. New cancer drugs are expensive no doubt. Yet they account for only account for 0.7 percent of the $2.9 trillion we spend on health care. Cancer spending has increased in 1995 from $42 billion to about $130 billion today. But its share of total health spending declined from 4.7 percent to 4.4 percent during the same time period.
In fact, new medicines reduce the cost incurred by a cancer diagnosis, for instance in part by reducing hospitalization. In 1996 drugs were 3.7 percent of cancer spending and 62.4 percent went to hospitalization. By 2012, drug spending was 9.3 percent of cancer costs while the share going to hospitalization dropped to 41.3 percent. During the same time period the life of expectancy of cancer patients increased, mortality rates declined by 20 percent and the number of cancer survivorship grew from 9.8 million to 13 million. The NCCN flashcards ignore these cost and life saving gains.
To be sure, the out of pocket cost of cancer drugs has increased. But the huge jump is caused by insurers and pharmacy benefit managers who force patients to pay up to 40 percent of the cost of a drug that two years only cost a few dollars a month. More recently, the percentage of health plans placing all drugs in the highest cost sharing tier has nearly doubled.
Capping cost sharing would require about people paying 50 cents more in premiums every month. Yet NCCN accepts insurer cost shifting as a fait accompli. It forces doctors and patients to choose treatments, not based on value, but on the insurer imposed cost of a medicine, a cost that is often based on how big a rebate other medicines generate.
Further, each NCCN flashcard measures one drug for one disease for an average patient. But often drugs must be used in combination to achieve results. Indeed, each “tumor may embody more than 100 different diseases, and multiple subtypes of each tumor exist. Even if some of these tumors have things in common, the individual landscape of each patient may be very distinct.”
Finally, the flashcards are to be used, it seems, to discourage the persistent hope for rescue in patients with life-threatening disease.
Hope is a valuable thing. For example, AZT, the first HIV drug, showed no additional survival in clinical trials. NCCN flashcards would deem them expensive but ineffective. In the real world, the use of such medicines kept enough people alive until the next generation of anti-AIDS extended life by years. The flashcard negates that value.
A survey of patients who chose assisted suicide in Oregon show that since 1998 the number of people citing the cost of care as a reason for their decision jumped 77 percent. To the extent that the NCCN flashcards reinforce the impact of insurer cost shifting and are skewed against persistent hope, they may contribute to an increase in cancer patients thinking there is no longer a reason of a value for living. Let's hope not!
Interesting and well-sourced article on the continuing saga of the CDC’s opioid guidelines and the conflicts of interest of the Core Expert Group.
The article is titled, Dysfunction, Lobbying, and Conflict of Interest in the Debate Over Opioids and here’s one quote to whet your appetite:
“I’m sure everyone on the committee is an expert, but you need to have a variety of opinions, otherwise why even bother having the meeting in the first place,” said Pitts, whose responsibilities at the FDA included overseeing the formation of FDA’s advisory committees. Referring to PROP’s role in creating the guidelines, Pitts said, “When you basically take one group that is considered the opioid lunatic fringe and allow them to create the basis of your policy almost verbatim is inexcusable. It’s bad policy. It’s bad science. It’s poorly serving the public health.”
The complete article is well worth a read.
California Governor Jerry Brown signed a “Right to Die” bill into law lastweek. Meanwhile, a state ballot initiative to impose price controls on medicines will insure that lots of people will take advantage of the law that otherwise would be alive.
That’s because price controls create shortages of important medicines, especially for cancer. And price controls add months, if not years for the time it takes to get medicines to patients. And price controls are always combined with steps to coerce patients to take cheaper medicines.
1. There is a right to die using an off-label combination of lethal drugs if you have a fatal illness. There is no corresponding right to try an experimental treatment if you are dying. You can get an experimental drug if the company making it will cover the cost. Setting prices artificially low even as the cost of developing new medicines increases means that the right to die will trump the right to try.
2. Similarly, we force dying patients to wait years for new medicines to become available. In addition to Food and Drug Administration regulations, insurers and health systems demand evidence that a drug is worth it. That demand makes people wait for many new medicines. Price controls are based on such ‘evidence’. It is self evident that the unnecessary delays in access contribute to the desire to take one’s own life. Price controls will and do affect the decision to die.
3. Finally, we are developing cost control mechanisms that reinforce the desire for assisted suicide. Price controls are accompanied by so called treatment pathways limit the use of new medicines until people fail on older, often more toxic drugs with more side effects. In an age of personalized medicine, it is possible to customize treatments to patients to extend life. Yet most pathways use average response to one drug. In turn, that average response – which will be far below what many people with an illness would experience – is used to measure the “value” of treatment.
Most people choosing assisted suicide have cancer. And most of the cancer patients who make that decision have tumors or cancer types that have shown the least progress over the past 20 years. At the same time, the percentage of cancer patients choosing assisted suicide has declined since 1998 as new treatments emerge. Indeed, in 1997 sixty-three percent of HIV patient assisted suicide, and 55% acknowledged considering physician-assisted suicide as an option for themselves. In Oregon the number of HIV patients chose patients choosing assisted suicide went from from 10 in 1998 to 0 in 2014. The key variable is access to new drugs – many of which were shown to provide benefits deemed not worth it by treatment pathways put forth by physician groups and insurers – that extend and improve life. So by delaying access to new medicines that might be effective we are encouraging assisted suicide.
Finally, the Oregon survey shows that the reason for assisted suicide with the biggest increase since 1998 is financial implications of treatment. The percent citing this cause jumped 77 percent. By extension, eliminating financial burdens would eliminate assisted suicide.
However, our health system is moving in the opposite direction. It is shifting the cost of medicines that offer hope to patients. In many cases insurers are increase the effective price of medicines by more than the 5000 percent increase that has been a source of outrage. Under price controls, insurers and government health programs would not be obliged to cover anyt medicine it believes is too expensive. What’s more, rather than fighting to eliminate that burden with copay limits, the leading cancer doctor and provider trade groups have made the insurer-imposed cost to the patient a key reason dying patients should choose one treatment or another or no treatment at all.
A system that delays access to new treatments, underestimates survival and deliberately exposes the dying to the cost of the potential most effective treatments and then hits the patient over the head with the expense (instead of protecting them from it) essentially makes it easier for the the sick and disabled to die. As my colleague Peter Pitts has noted, in Oregon Medicaid denies coverage for certain cancer treatments for patients that have been deemed “too” sick, haven’t responded well to previous treatments, or can’t care for themselves.
Oregon state bureaucrats are severely restricting access to care and dooming potentially thousands of local patients to a premature death with medicines the state will gladly provide free of charge.
We have a health system that is turning the right to die into a duty to die. Price controls will make it virtual requirement to do so.
Much debate over the manner in which the CDC handled conflicts of interests with its opioid guideline development team.
And there’s going to be a lot more.
The Annals of Internal Medicine has just published its Principles for Disclosure of Interests and Management of Conflicts in Guidelines.
In the very first paragraph, the guidelines warn against …
"Intellectual COIs, including attachment to ideas or academic activities that create the potential for an attachment to a specific point of view." Specific examples of this are listed as, “community standing,” “personal convictions or positions,” leadership or board committee memberships” and, “Leadership or board, or committee memberships.”
And who appears on the CDC’s Core Expert Group? Jane Ballantyne.
(PROP), a controversial organization that has lobbied Congress and criticized the Food and Drug Administration for not doing more to limit opioid prescribing. And in her conflict disclosure (see page 39 of the CDC document), she discloses her services as a paid consultant to Cohen Milstein Sellers & Toll – the same law firm referenced by the as shopping around opioid litigation – and having guidelines from the CDC that recommend restrictions in opioid prescribing could certainly be advantageous to such an endeavor.
As Pain News Network has reported, “The CDC and PROP appear to have a close working relationship — a link to recommending “cautious, evidence-based opioid prescribing” can be found — unedited — on the .
According to Bob Twillman, Executive Director of the (one of the stakeholder groups that will be consulted by the CDC):
Clearly, this is PROP’s way of getting what FDA didn’t give them when they advocated for an ER/LA opioid label change. I don’t think it’s a coincidence that this sets a 90 mg MED dose limit, when PROP advocated for a 100 mg MED dose limit in their Citizen Petition to the FDA. That PROP’s president and one vice-president are part of the core expert group; their executive director and a board member are part of the stakeholder review group; and another board member is one of the three who will help edit the guidelines after the stakeholders report, all is not a coincidence, and clearly puts their fingerprints all over this guideline. But, of course, no one is supposed to know that.
On every count the CDC fails the test of intellectual conflict of interest. According to the CDC, they agency “aimed to minimize conflict of interest, enhance objective assessment of the evidence, and reduce bias.” Well, they may have aimed – but they missed badly. The members of this group do not represent a broad spectrum of thought on opioids. To put it nicely, the issue of normative bias needs to discussed –loudly and openly.
The complete guidelines from the Annals of Internal Medicine can be found here. It should be mandatory reading at the CDC.