FDA's New Guidance on Clinical Monitoring Arrives

The FDA has released its long awaited update and replacement to the outdated 1988 guidance on clinical monitoring.  The draft guidance for industry on Oversight of Clinical Investigations - A Risk Based Approach to Monitoring is early evidence that the findings and recommendations of the Clinical Trials Transformation Initiative (CTTI), FDA's public-private partnership with Duke University among others, are beginning to take hold in practice in the clinical trials domain.

According to a CTTI survey, clinical trial sponsors are successfully employing a range of monitoring modalities, such as centralized monitoring by biostatistical and data management personnel, targeted on-site visits to higher risk sites as well as frequent on site visits to all sites by clinical monitoring personnel.  Yet historically, industry sponsors have rarely relied on any mechanism other than comprehensive all-site monitoring performing 100% source data verification, every four to six weeks.  It is a well-understood, costly and time consuming method of monitoring that the industry perceives is preferred by FDA.  Yet, given the vast changes in the clinical trial landscape in the decades since the FDA's previous 1988 guidance and the regulations covering sponsor obligations, including the increase in the number and complexity of clinical trials, investigator experience, changes in ethical oversight, treatment options, and geographical dispersion of clinical trial sites, the FDA now calls on the industry to employ new and more effective methods for monitoring clinical trials.  

This is big news.  As in the recent final rule on safety reporting, which requires sponsors to make judgments about whether a single case is instructive enough to warrant reporting to the authorities, FDA here is encouraging sponsors to reduce their reliance on a one-size-fits-all, on-site, 100% source data verification comprehensive monitoring approach in favor of a more diversified, horses-for-courses approach, building monitoring plans and employing monitoring modalities based on multiple factors such as:

·           type or study and endpoints (whether objectively or subjectively derived)

·           disease state of patient population

·           sponsor experience with investigator and investigator experience with research

·           complexity of protocol, such as adaptive designs, stratified designs, complex dose titrations, etc.

·           availability of EDC to facilitate centralized monitoring

Throughout the guidance, the FDA continually refers to the prevalence of electronic data capture (EDC) that allows for centralized and risk-based monitoring.  It appears that their expectation is that EDC usage is now or very soon will be the norm rather than the exception.  This is certainly one of the most important advancements in clinical trials technology that allows for alternatives to comprehensive on-site 100% monitoring and indicates that despite its earlier struggles for acceptance during the 1990s, remote data capture is here to stay at last.

While this is a draft guidance, the FDA is putting teeth into it by:

·           withdrawing the extremely outdated 1988 guidance

·           ensuring that BIMO guidance manuals are compatible with the recommendations

·           ensuring affected areas of FDA are aware of the goals of the guidance

·           will consider establishing processes within CDER for sponsors to voluntarily submit feedback on proposed monitoring plans.

It will be interesting to watch how sponsors and CROs implement this new guidance. Having traditionally supported comprehensive, frequent on-site monitoring methodology, CROs will have to develop new pricing models other than X monitors spending Y days onsite every Z weeks.  Sponsors by their turn will have to revise their SOPs and employ different kinds of training to use centralized electronic monitoring methods efficiently.

This post was published at the Clinical Leader site.  I am grateful to Rob Wright, Chief Editor of Life Science Leader magazine for his support.

Followup to the Makena/KV Pharma Saga

Sometimes the little guy wins.  Sometimes it pays to stand up and fight back.  That's what has happened in the case of KV Pharmaceutical and its Makena, a form of progesterone indicated for preventing premature birth and approved by the FDA recently under the Orphan Drug Act.  This blog has addressed this twice recently, here and here (scroll down).  The injectable form of the drug, for which no one holds a patent including KV, has been available for decades from compounding pharmacists at a cost of $10-20 per week for weekly injections during critical weeks of gestation.  Under the Orphan Drug Act, KV Pharma was able to augment the available clinical research with some additional clinical data and obtain approval for sale under accelerated review, and receive considerable government assistance (read: tax breaks), plus 7 years' market exclusivity, for a product on which they don't hold a patent and in which their development investment was relatively low.  Meanwhile, KVeliminated the competition - the compounding pharmacists - by sending them letters stating that under the terms of their approval, the FDA would no longer 'exercise enforcement discretion with regard to compounded versions of Makena."  KV priced the product at a whopping $1500 per weekly injection - and neither the FDA nor any other arm of the US government controls drug pricing in this country - made some weak noises about providing assistance to certain women, and thought that was the end of that. 


Not so fast, say the patients and their physicians.  Public response to this story has been swift and loud.  A sampling of coverage of the outcry is at the bottom of this post.  Patients and physicians were outraged at KV's wantonness in so drastically inflating the price by a hundred fold, and their rationalization that weekly dosing would still cost less than a stay in the NICU fell on unsympathetic ears.


Not so fast, also says the FDA.  In a statement released today on FDA's web site, the FDA makes it clear that while it cannot tell KV how much to charge for their product, it indeed can exercise its enforcement discretion and will not come after pharmacists that "compound hydroxyprogesterone caproate based on a valid prescription...unless the compounded products are unsafe of substandard quality", or not compounded according to proper technique.


According to FiercePharma, KV has yet to comment on the FDA's statement and it is not yet clear what effect if any this will have on pricing.  


http://www.fiercepharma.com/story/payers-may-balk-makena-pricing-kv-says/2011-03-23
http://www.fiercepharma.com/story/senators-demand-ftc-probe-kvs-makena-pricing/2011-03-21
http://www.fiercepharma.com/story/kvs-makena-delivers-1500-sticker-shock-docs/2011-03-10

KV Pharma and the Drug Price Wars

At the bottom of my last post I looked at the recent case of KV Pharma and its new drug Makena, which was approved last month by the FDA under the Orphan Drug Act for prevention of premature birth.  Makena is a form of progesterone that has been available for decades at a cost of $10-20 per week from compounding pharmacies, but now KV Pharma, which went to the trouble of registering their version of the product has a 7 year monopoly on sales of the product (thanks to the Orphan Drug Act), which they have priced at $1500 per injection.  The drug is dosed weekly from weeks 16 through 20 of gestation.  The penalties associated with trying to provide the compound the old way should give any pharmacist reason to think twice.

Two US Senators (Amy Klobuchar, D-Minn and Sherrod Brown, D-Ohio) have asked the Federal Trade Commission to look into the pricing matter and investigate whether the $1500/injection price tag constitutes anti-competitive behavior.  The senators also charge that KV Pharma's patient assistance program is insufficient.  You can see the press release and letter, which uses words like 'price gouging', here.


As is often the case, Pharmalot is all over this.  This week they asked for an explanation from Jamie Love of Knowledge Ecology International.  Love points out a number of issues stemming from the use of the Orphan Drug Act to secure this approval along with its exclusivity.  The Orphan Drug Act was originally enacted to incentivize manufacturers to make otherwise unprofitable medicines available for diseases that strike relatively few patients.  In the case of Makena, the compound was already available to pregnant women since the 1950's.  So even though KV Pharmaceuticals did perform clinical trials, and the rest of the research was done by the NIH (see here for the full list of trials), and KV does not hold the patent on the progesterone compound (hydroxyprogesterone capoate, apparently no one does according to the Orange Book), they still receive the seven-year market exclusivity under the law.  The Pharmalot Q&A with Love is here, which includes links back to their earlier coverage of the story.  Love's blog noting how the Orphan Drug Act could be improved is here.

FDA News Roundup

The FDA was in the news a lot this week, an especially noticeable series of events if you have multiple searches returning FDA news each day as I have.  Reviewing my Twitter feed alone (follow me!), I linked to six separate news items about the FDA the last four days:

• Feb 11 - FDA to contract out more foreign inspections from FiercePharma
• Feb 11 - An evidence-free and detail-light op-ed in The Hill's Congress Blog written by Newt Gingrich*, GOP 2012 presidential hopeful; Andrew C. von Eschenbach, former FDA commissioner appointed by Bush 41; and Wayne Oliver, former Georgia Pharmacy Association lobbyist and current head of Gingrich's Center for Health Transformation, a "think-tank" for health care and FDA reform.
• Feb 10 - An op-ed by Rep Joe Pitts (R-PA) claiming that the new proposed FDA medical device regulations are driving innovation and jobs to the EU.
• Feb 10 - FiercePharma again, this time linking to an NYTimes op-ed by Ian D. Spatz, former Merck exec, writing about how direct-to-consumer ads are an important public educational tool that can reduce side effects.
• Feb 9 - a press release from the House Appropriations committee with proposed budget cuts of $220M from FDA's budget for 2011, around 7% of its requested $3.2B in 2010.
• Feb 9 - A Wall Street Journal article noting FDA's concern over six different companies not completing their follow up commitment studies they promised to conduct following accelerated approval of their products.

Bringing all these stories together into some sort of context I leave to others.  One does note that the "over-regulation is hurting business" meme was in heavy rotation this week.

*Newt has been after the FDA for a long time.  In 1994 as Speaker of the House, he advocated "nuking" the FDA altogether and replacing it with a combination of third party reviewers and corporate tax incentives. (Authentic Leadership: Rediscovering the Secrets to Creating Lasting Value, William W. George; Jossey-Bass, 2003)

FDA Approves Depressant Drug For The Annoyingly Cheerful

A little something for your Friday...

Informed Consent May Be Compromised & Medical Device reform

In a study published today in IRB: Ethics and Human Research (free abstract, $ subscription for full article), concluded that unrealistic optimism is prevalent among some clinical study subjects  and that it "has the potential to compromise informed consent".  Seventy-two early phase cancer study subjects completed questionnaires designed to assess their level of understanding of the study's purpose as well as to detect signs of unrealistic optimism.  Unrealistic optimism is defined as "specific to a situation and consider (sic) a form of bias...and is distinct from "dispositional optimism, which is a general outlook on life and is neither realistic nor unrealistic".  Questions to reveal unrealistic optimism revolved around the likelihood of particular individual outcomes as compared with other study participants, or the participant's tendency to give greater weight to possible benefits than possible risks.  According to the study's findings, 72 percent of the subjects accurately understood the objectives of the cancer trial in terms of potential benefits to future cancer patients rather than directly to themselves, which means that 28% of respondents did not clearly separate those facts.  The researchers' concluded that we need to improve the informed consent process by "paying more attention to how patients apply the consent information to themselves".  Reporting on the trial is found online at Medical News Today.  


In other news, last week the FDA announced proposed changes to improve the agency's 510(k) program for approving medical devices for sale.  Some of the recommendations include:

• consolidate the terms “indication for use” and “intended use” into a single term, “intended use”; 
• expand its statutory authority to consider off-label use when determining the intended use of a device; 
•  issue guidance on when a device should no longer be available for use as a  predicate;  
•  issue a regulation on its rescission authority;  
•  issue guidance to create a “Class IIb”; and  
•  seek greater authorities to require postmarket surveillance studies as a condition of clearance for certain devices.

The full report is here (PDF).  FierceMedicalDevices reported generally favorable reception of this news by the industry.  We have a long way to go until any of the report's recommendations become regulation, but now at least we have some ideas of which way the agency's thinking is going.  At the same time, the Wall Street Journal carried an op-ed by President Obama discussing the balance between regulator and free market. It all makes for very interesting reading.

Thalidomide and Public Perception

Thalidomide's left and right enantiomers

Yesterday on Slate.com, a piece was posted entitled Thalidomide's comeback: Who'd have thought the drug would have a second life?  The piece first briefly - very briefly - reviews thalidomide's dark past as a sedative and treatment for morning sickness - not a great idea for a drug with a powerful teratogenic profile  - in the 1950's and 60's and the resultant extreme fetal damage followed by the drug's banishment into the wilderness for a biblical 40 or so years of wandering.  The piece relates the oft-told - and some say apocryphal - story of the FDA's heroic stopping of the the drug on US shores before it could become approved and wreak its havoc here. In the late 1990's the drug was resurrected and rehabilitated, first as a treatment for a complication of a form of leprosy (free; registration required), then in 2006 as first line treatment for multiple myeloma.  Researchers studied the cancer indications initially because of thalidomide's inhibition of blood vessel development, although now scientists are downplaying that hypothesis and looking at the drug's ability to boost the body's malignancy-hunting immune cells, which is leading to possible indications such as lupus and others.  As a condition of approval, FDA required thalidomide's new owner Cellgene to develop an education program for prescriber, pharmacist and patient so that everyone understood the risks and took the proper precautions.  (I have a copy - I knew Cellgene's local sales rep a few years ago.)  The post author then questions why, in the face of such compelling safety concerns, the FDA would "give it another chance", and notes that the target population, at least those with multiple myeloma, is most likely to be people who are of an age to remember thalidomide and its damage.

What I find interesting about stories like these is the premise that the drug itself is somehow an actor, a party to the conflict, that there is such thing as a "good" or "bad" drug, and that a "bad" drug should somehow be punished by never being used for any good purpose.  Drugs aren't bad or good; they are just chemical compounds with learn-able and predictable behaviors.  Develop a chemical compound that interacts badly with the human body's own chemistry and bad things will happen.  Develop a compound that heals or helps the body perform its homeostasis chores and, as long as you know or can predict what the side effects are and manage them, good things will happen.  The question really should not be: why did the FDA give thalidomide another chance; it should be why not?  More people are suffering from cancers and other life-ending diseases than ever before.  Why would we not want to use all the tools in our toolbox?  An ax can be used to cut down firewood or to damage the backyard fence.  We don't cut our firewood with a butter knife simply because an ax has potential for damage.  We learn the productive uses for the ax while protecting ourselves by keeping it is a safe place and making sure we know how to use it.  Likewise, we can learn how to predict the behavior of chemical compounds and then target them at the stuff making us sick.  Or use them to help keep us well.  

Thalidomide is not a "bad" drug any more than is acetaminophen.  The box of cold medicine I bought yesterday over the counter loudly advised me to review the new warnings that if I take too much acetaminophen in a 24 hour period I could suffer life-threatening kidney damage.  There was no prescription required, no pharmacist advising me of the risk and verifying that I understood it. Thalidomide on the other hand is carefully prescribed for people with a specific condition and who are inform why it should not, must not, be used by pregnant women or women who might become pregnant - which is not a very big subset of multiple myeloma patients in any case; procreation is just not their main concern.  The number of people who buy cold medicine each year must be orders of magnitude than the number of people who are prescribed thalidomide, and the potential for kidney damage from overdose of acetaminophen seems to be far greater than the danger of another wave of thalidomide-induced birth defects.  Yet we're not reading blog posts about the dangers of OTC cold medicines.

What people really should be thinking about is not "bad" drugs, but the fact that any drug from aspirin on up can have bad side effects, even when used as directed.  One of the reasons it takes so long for a new drug to make it through the research cycle is that it takes a long time to identify potential side effects and learn how to adjust dosing to minimize them.  People sometimes think that once a drug is approved it must be completely safe, and they get upset and look to haul someone into court for damages if they suffer an adverse effect - check out the comments to Slate's thalidomide post to get a flavor of this.  But that's not what approval means.  Approval simply means that the risk:benefit ratio appears to favor the benefit side; it never means that the risk has been completely eliminated.  

Whether the FDA really did sniff out the problems from the data alone or whether the submission was passively awaiting review when the feathers hit the fan in Europe as some regulatory old timers have suggested, is something we will probably never know for sure.  The bottom line is that a drug that was not safe for the indication sought in the application, that of morning sickness, was kept off the US market and a new a high standard for safety evaluations of every drug that came after it was set.  Even the law governing drug evaluations was changed in the wake of the thalidomide disaster; the 1962 Kefauver-Harris amendments changed the Food Drug and Cosmetic Act - the law that gives the FDA its teeth - so that drug manufacturers would have to demonstrate both safety and efficacy to win US marketing approval.  It is really hard to come up with a cure or treatment for a disease and it should be.  

Has Clinical Trial Globalization Run Its Course?

A few weeks ago I had the good fortune to participate in a very interesting panel on just that topic at MAGI's Clinical Research Conference in San Francisco.  The session was chaired by Joan Chambers, COO of CenterWatch, and my panel mates were Kamran Ansari of Sanofi-Aventis and Nye Pelton of Eli Lilly.  I jumped at the chance to be on this panel because I have noticed that the recent, breathless you-heard-it-here-first pronouncements coming out of the CRO industry hearkening a great tidal wave of clinical studies to places like India, South America, Russia and Central European countries have not quite panned out.  The studies are still going to those places but not exactly in the free-for-all we were led to expect.  Does this signal that globalization has peaked, and if not, what adjustments should we make in our expectations, especially those of us with a strong international expertise component in our business models?

My view is that we are experiencing a pause in the marketplace, if not quite a correction, and we will start to see increased movement again quite soon.  I think the pause occurred for a couple of reasons: one) performance did not quite measure up to the claims of some providers, and two) the worldwide financial meltdown took an awful lot of business with it in the form of reigned in development programs and planned studies that never got started to save precious cash.  Let's look at the first reason, since this is not an economics blog.

In the first half of the 'aughts' or the decade just ended, I attended a lot of informational meetings and conferences on emerging markets and heard many vendors explain how they had so harmonized their processes, so locked in the regulatory pathways in each country that sponsors could entrust their studies to these vendors safe in the knowledge that the conduct and resulting data would be of the highest quality and the entire experience would be as painless as if the study were being run in the US or EU.  Which is many things but painless is not one of them.  And which inevitably turns out not to be true anyway.  Sponsors experienced some significant buyer's remorse when they discovered that their project manager was not the person who came to do the bid defense; that the data, ethics, and medical practice standards could be very different in actual countries of conduct and required an experienced hand in the design phase of the protocol, not just the conduct and reporting phases; that their data were being collected many time zones away by people who the sponsor had never clapped eyes on.  Instead of finding the experience painless, many sponsors felt unease with the entire process even when the data and trial results proved to be of high quality - they didn't quite trust what they saw because they didn't know who was running the trial - there was no relationship.  Vendors who were paying attention have now retooled their presentations to highlight the relationship side of the business.

Even the FDA has got on the bandwagon of mistrust.  A recent Pink Sheet ($) dated October 4, 2010 published findings by CDER's Office of Biostatistics that showed in 13 of 16 large multinational cardiovascular outcome trials, the measured drug efficacy was lower in the US than outside.  Four drugs studied in these trials were not approved specifically because of this 'regional heterogeneity' and nine of the drugs were deemed approvable but required more data.  Anecdotally I have seen this type of regional difference myself and have always interpreted it as proof of the quality of the conduct, the high acceptability of the data.  FDA says not so fast.  Some regional differences in treatment effect may be expected, but too much can arouse concern.  The Pink Sheet report cites examples such as the extended release version of metaprolol (AstraZeneca) whose 'effect on mortality was virtually all outside the US"; AZ's ticagralor which demonstrated no effect in US patients, only exUS; and whether anti-epilepsy drugs bring an increased risk of suicidality, where studies showed that outside the US, suicidality was higher.  Bridging studies, even PK/PD or surrogate studies may be indicated to explain regional differences that are not entirely due to chance.

In discussion amongst our panel and with the attendees, it seemed that at least based on the interest in the room, globalization is not dead yet. We all agreed that training, relationship, close monitoring, realistic expectations and appropriate study design are all important factors in running successful, evaluable international clinical trials.




photo credit: J. Mardell, 2010