The 2st Century Cures Act: Patient Experience in Drug Approval

On Thursday, May 19, 2015, the Energy and Commerce Committee of the House of Representatives voted 51 to 0 to approve the 21^st Century Cures Act (“the Cures Act”) which would, if passed by the full House and Senate and signed by the President bring about a number of significant changes in NIH research funding, the process of drug development, and the FDA review of New Drug Applications (“NDAs”). Because the current draft is 300 double-spaced pages in length the focus in this post will be on just six of those pages--“Sec. 2001. Development And Use Of Patient Experience Data To Enhance Structured Risk-Benefit Assessment Framework.” While there are likely to be some changes to the current draft, given the overwhelming bipartisan support in the House, it seems that much, if not all, of the current draft will become law.

Section 2001 of the Curs Act consists of two subsections, currently denominated (x) and (y).  Section 2001 would appear to require very little change to the current approach of the FDA to drug approval.  Section 2001 Subsection x (1) states that “The Secretary shall implement a structured risk-benefit assessment framework in the new drug approval process [A] to facilitate the balanced consideration of benefits and risks; and [B] to develop a consistent and systematic approach to the discussion of…the benefits and risks of new drugs.” The current draft of Sec. 2001 Subsection (x) 2 contains the proviso that “Nothing in Paragraph (1) “shall alter the criteria for evaluating an application for premarket approval of a drug.” The apparent focus of this subsection (x) is to bring greater clarity and consistency to the FDA’s weighing of risks versus benefits. This is an unobjectionable goal, if somewhat difficult to implement. For example, one cancer drug may cause severe skin reactions while increasing overall survival by one month, while another drug for the same form of cancer may cause severe gastric effects while increasing overall survival by 1.2 months. Comparing the risks and benefits of those two drugs is obviously difficult to do.  It is that difficulty that may be the objective of the much more interesting Subsection (y).

Subsection (y) is entitled “Development And Use Of Patient Experience Data To Enhance Structured Risk-Benefit Assessment Framework.”  Subsection (y) 1 requires the Secretary of HHS, over a period of 2 to 3 years, to a promulgate a number of guidances and establish procedures by which non-NDA sponsor entities may submit patient experience research proposals for feedback from the Secretary as well as patient experience data and data analyses.  Patient experience data, or, as it is also known, patient-reported outcomes data has been a field of interest in clinical research for a number of years. Patient-reported outcomes was the subject of an FDA Guidance issued in 2009 (“2009 Guidance”).  The 2009 Guidance recognized the value of assessing patient experience endpoints in clinical trials and encouraged patient input in developing the instruments to be used in assessing patient reported outcomes or experience:

Item generation should include input from the target patient population to establish the items that reflect the concept of interest and contribute to its evaluation. The population will help generate item wording, evaluate the completeness of item coverage, and perform initial assessment of clarity and readability.

However, the approach to patient experience data in the Cures Act goes well beyond the 2009 Guidance.  Subsection (y) provides the Cures Act definition of patient experience data:

In this subsection, the term ‘patient experience data’ means 
data collected by patients, parents, caregivers, patient advocacy organizations, disease research foundations, medical researchers, research sponsors or 
other parties determined appropriate by the Secretary that is intended to facilitate or enhance the 
Secretary’s risk-benefit assessments, including information about the impact of a disease or a therapy on patients’ lives.

The statutory inclusion of data collected by “patients, parents, caregivers, patient advocacy organizations, [and] disease research foundations” is radically different from the drug-sponsor driven approach that was addressed in the 2009 Guidance. Bringing data collected by persons or entities other than the drug sponsor into the New Drug Approval process (or the sNDA process of approving additional indications or major label changes) would be a fundamental change in the concept of data to be used by the FDA in new drug review and would significantly increase the role of patients and patient organizations in the drug approval process itself.  If so, the 21^st Century Cures Act’s effect on drug development might be as dramatic as the title of the Cures Act suggests.

What Is Pharmaceutical Policy and What Is Its Goal?

Pharmaceutical policy is the role that government plays in determining the rate at which new drugs are developed, what drugs are developed, who has access to the drugs that are developed, and the choice of drugs by doctors and their patients. The goal of pharmaceutical policy is to provide the maximum benefit to health for whatever amount is spent on pharmaceuticals.  A good policy in any area of health care will produce the most health at the least cost. This first premise, although it may be new to some of you, is a generally accepted premise of public policy analysis: more of a good thing is better than less (whether it be educational levels, health, or economic production) and getting more of a good thing at the least cost is better, as that leaves the surplus to be allocated to obtaining more of other good things (so getting more health for less dollars would allow us to spend more on schools, for example).

The Need For Publicly Funded Trials To Get Unbiased Comparative Effectiveness Data

By Bob Bohrer

Originally Posted on Health Affairs by Robert Bohrer On February 20, 2015 http://healthaffairs.org/blog/2015/02/20/the-need-for-publicly-funded-trials-to-get-unbiased-comparative-effectiveness-data/

Comparative effectiveness research was one of the hotly debated components [1] of the Affordable Care Act. The pharmaceutical industry is marketing driven, with pharmaceutical companies spending more on marketing [2] than they do on research and development. The need for a marketing edge can also drive drug development.

As illustrated by the discussion below of Gazyva and Nexium, drugs can be developed at higher doses than the drugs they are intended to replace. When the newer, higher-dose drugs are tested against the older, lower-dose drugs, the trials are intended to show that the newer, higher dose drugs are superior to the older drugs that will soon be available as a biosimilar or generic.

It can be very difficult to tell whether the results of such trials reflect the differences between the active ingredients or simply the difference in doses, but such trials are almost certain to lead to increased use of the newer, higher-priced drugs. Because the money at stake creates such an incentive for companies to stack the deck, publicly funded trials are the only way to make sure that evidence-based medicine is based on the best possible evidence.               PDF of this post

Interesting Developments in November

 I will be commenting soon on developments related to pharmaceutical patents and their significance for personalized medicine, but in this post I am briefly describing several interesting news items and articles from various media sources, and I am attaching links to the stories and articles.

1.  Jonathan Darrow has written a great article entitled Pharmaceutical Gatekeepers in the Indiana Law Review.  Darrow looks at the variety of actors in the drug-use decision-making process and their roles in the continued consumption of ineffective drugs.

http://mckinneylaw.iu.edu/ilr/pdf/vol47p363.pdf

2.  The Tufts Center for the Study of Drug Development has released its latest estimate of the cost of developing a new drug and, as always, the estimate, $2.6 billion, is a stunning one that has attracted widespread media attention.  I think the most nuanced mass media report on the study was written by Aaron E. Carroll and published in The New York Times on November 19th.

http://www.nytimes.com/2014/11/19/upshot/calculating-the-real-costs-of-developing-a-new-drug.html

3. The issue of clinical trial data sharing has been the focus of significant attention over the past several years.  In the November 27^th issue of The New England Journal of Medicine, Brian L. Strom et al published a report of the results of GlaxoSmithKline providing full access to its clinical trial data as of May 2013, and the NIH has proposed a new rule requiring increased access to clinical trial data summaries for all clinical trials.

            The Strom article is here:

            http://www.nejm.org/doi/pdf/10.1056/NEJMp1411794

            The NIH’s notice of its proposed rule is here:

            http://www.regulations.gov/#!documentDetail;D=NIH-2011-0003-0003

4.   Finally, the issue of pharmaceutical pricing continues to be in the news and on November 25th Robert Langreth of Bloomberg/BNA published an interesting article on pushback by Express Scripts and other pharmaceutical benefit managers (PBMs).  The PBMs are revising their formularies and their access requirements for specialty drugs in an effort to hold down costs. 

http://www.bloomberg.com/news/print/2014-11-25/more-medicine-goes-off-limits-in-drug-price-showdown.html

Pricing has been the biggest story in the pharmaceutical world in 2014, I expect that to continue in 2015.  The PBMs’ efforts to hold down prices and the soon to emerge marketplace for biosimilars in the U.S. will certainly be an interesting part of the pricing story.

Update on Generics, Labeling, and Liability

                           

I began this blog back in February of 2014 with two posts on the FDA’s proposed changes to the rules for generic labeling and the issue of potential liability of generic drug manufacturers for failing to strengthen their warnings when it would be appropriate to do so. Recent events related to generic labeling and liability warrant a brief update on the issue. In litigation over injuries allegedly attributable to Reglan and its generic form, metoclopramide, a New Jersey appellate court has ruled that generic manufacturers could be liable for failure to warn when they had failed to update the label for their drugs even after the brand name manufacturer had added a new warning.  In other words, the New Jersey court held that actions for failure to warn were not preempted under the rule in Pliva v. Mensing, because in Pliva the defendants were required to adhere to the brand name drug’s label and in the case of metoclopramide the problem was the failure of some generic manufacturers to update their labels when changes were made to the brand name label.   

The second development on this issue is the news that the FDA is postponing action to finalize the proposed rule.  The FDA’s postponement of its final action on the rule comes in the wake of an interview with Regulatory Focus in which Ralph Neas, the President of the Generic Pharmaceutical Manufacturers’ Association, said that the Association was readying a lawsuit if the FDA adopted the proposed rule. The FDA has only said that it had received a very large number of comments on the proposed rule and that the Agency is committed to giving all comments serious consideration. This issue remains a hot one and the recent change in the balance of power in Washington only raises the temperature further.   

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Profits, Ebola, and Biodefense-- Common Ground for the New Congress

In my post of November 6, 2014, I linked to an interesting BBC story that pointed out that pharmaceutical companies are highly profitable in comparison with other industries and that pharmaceutical companies generally spend more on marketing than on research and development (in the case of Pfizer 72% more and in the case of Novartis 47% more).  This is unfortunate, but inevitable when companies with very similar drugs and relatively little data that support a physician’s preference for one drug over another are fighting for market share.  At the same time, pharmaceutical companies are being criticized for their high prices and for their slow pace of investment in developing drugs and vaccines for Ebola.  The New York Times on October 24, 2014, provided extensive coverage of a number of Ebola issues, including a story on a vaccine that had shown great effectiveness in a primate study but then had gone undeveloped for ten years.  The New York Times story pinned the blame for the delay in development on the lack of a significant commercial market for the vaccine.  The Director-General of the World Health Organization (WHO), Dr. Margaret Chan, had this to say in her November 3^rd address to the WHO Regional Committee to Africa:

The second argument is this. Ebola emerged nearly four decades ago. Why are clinicians still empty-handed, with no vaccines and no cure?

Because Ebola has historically been confined to poor African nations. The R&D incentive is virtually non-existent. A profit-driven industry does not invest in products for markets that cannot pay. WHO has been trying to make this issue visible for ages. Now people can see for themselves.

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Interesting BBC News Story on Pharma Profit Margins and Marketing Expenditures

The story link is here.  As I have often said on the subjects of profits, companies charge prices calculated to maximize their profits.  And, as to the high marketing costs, when there isn't solid data to support a choice among similar drugs, marketing costs will inevitably rise.

Personalized Medicine Update

Personalized medicine uses an individual patient’s variations with respect to one or more biomarkers or combination of biomarkers to determine which is the most appropriate pharmaceutical or medical intervention.   Such biomarkers can be genetic variations or other variations.  In Mayo Collaborative Services v. Prometheus Laboratories (Mayo v. Prometheus) the “biomarker” was the level of the metabolite in a patient who had been given a thiopurine drug, and the Supreme Court held that a patent that taught how to adjust the drug dosage after measuring the metabolite was invalid as an attempt to patent a natural phenomenon.  After one of Myriad Genetics’ patent claims related to gene sequences used in its genetic test for breast cancer risk was similarly invalidated as a natural phenomenon or product of nature, the biotech and diagnostic industries were understandably concerned.  Personalized medicine is clearly a vitally important area for future healthcare and the extent to which the difficulty of obtaining intellectual property protection for pharmacogenomic testing or other personalized medicine assays could delay or undermine progress in the area is a question of great importance.  The North Carolina Journal of Law and Technology recently devoted a symposium to the question of the significance of the decision in the Myriad case and Chris Holman’s contribution to that symposium, in which he considers the potential impact of Mayo and Myriad on personalized medicine is particularly worth reading.

What the Market Will Bear: Pricing Pressures and Pharmaceutical Value

Until recently, the high prices of drugs seemed to be something like the weather—something people complained a lot about, but about which nothing could be done. That may be changing.  I think the push-back on drug pricing is reaching new levels and both the pharmaceutical industry and its chief lobbying group, PhRMA, are showing concern and taking action.  Examples of the pushback on pricing can be seen in this CBS 60 Minutes clip and in this article on Gilead’s pricing of its newer-than-Sovaldi combination Hep C drug Harvoni.  The level to which this rising criticism of drug prices is causing PhRMA to be seriously concerned can be seen in its post-60 Minutes statement and in this video  and accompanying text about treatments for cancer and in this shot across the bow of critics of drug prices.  PhRMA is even suing the U.S. Department of Health and Human Services over a rule that requires Orphan Drugs that also have non-Orphan Drug uses that are priced at a discount, to be sold the discount price even when a hospital uses the drug for the Orphan use. I will address this PhRMA Orphan Drug suit in a future post.  The pharmaceutical industry lobbying group is clearly pulling out all the stops to make the case that pharmaceutical R&D is a very costly enterprise and that expensive drugs are well worth their high prices because of the health benefits they provide.

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Cancer Drugs, Survival, Research Priorities, and the Human Condition

It is fundamental to human nature to hope, and one manifestation of this aspect of human nature is the desperate but understandable desire of cancer patients with very grave prognoses to look for a glimmering possibility of beating the odds. In this post I will look closely at the data on an anti-cancer antibody may have incrementally raised the bar in the treatment of one particularly grave cancer and discuss how this and other similar cancer drug development fits within the current framework of healthcare delivery and reimbursement.