Super Busy

My time has been largely booked with work. Travel has been quite extensive. In-house projects have been non-stop. As a result, there hasn’t been much time left for discretionary writing (i.e., this site). There is a light at the end of the tunnel, however.

Our HR group has posted a new position for our group (and another has tentative approval for 3rd/4th quarter). If you have any interest in Celgene, stop by the website and look in the Careers section…or drop me a line (my email address is in the comments below).

Bringing on more resources will definitely help out and hopefully clear some time for some writing. I’ve been thinking about a good number of topics that would make good discussion points. With any luck, I’ll have them up here soon.

TJK

21 CFR part 11 Update

Folks, it looks like some of our US regulations and guidance documents have been flagged for update by FDA….including everyone’s favorite, 21 CFR part 11 (source Cerulean’s email newsletter). I don’t anticipate major changes, just clarification on their intent.  Everyone enjoy your Friday.

New Guidance Agenda for 2009 Released by FDA

The FDA’s CDER has published its list of expected guidance documents and revised regulations to be issued this year (2009).

Readers of our 2009 forecast will find many items on the list familiar:

· 21 CFR Part 11

· Process Validation

· Adaptive Clinical Trial Design

· Contract manufacturing

· Various marketing, promotional and labeling guidance

· “Dear Healthcare Professional Letters” for recalls

TJK

Server Crash – what would the impact be?

I was reading Eric Zeman’s post on the recent Nokia server crash in which *data was lost*.

Server Crash Deletes 3 Weeks’ Worth of Nokia User Data

posted Yesterday, 12:35 PM by Eric M. Zeman
updated Yesterday, 1:40 PM

Updated: clarified which Ovi service was affected.

A cooler problem at one of Nokia’s facilities led to a series of catastrophic failures that ended in crashed servers. The servers in question housed user data from Nokia’s Contacts on Ovi service including contact information, photos and other data that had been synced from end-user handsets to Ovi. Despite Nokia’s attempts to repair the problem, the most recent back-up it could restore was dated Jan. 23. Anything uploaded or synced between Jan. 23 and Feb. 9 was completely lost. Nokia apologized for the problem and asked users to give it a second chance.

Now, these are guys who know technology….who know what they’re doing. If they can lose data, anyone can….what impact would this have on a Pharma company? Data losses are not acceptible in this field. This fits in the “things that make you say hmmmm” category for Pharma and related industries.

~TJK

The Impact of Kindle

I did it. I pre-ordered my father a Kindle-2 from Amazon.com for his Birthday/Father’s day. It has to be a combination gift in terms of two holidays as well in terms of multiple purchasers (Brother and Mother are pitching in too) because my Dad would go through the roof if he knew we spent the $359 on him….especially on a technology purchase.

And though both his Birthday and Father’s Day are months away, I don’t have much to worry about him finding out as he’s not online…at all. His exposure to the internet consists of my mother showing him grandchildren pictures that I send to her. Sometimes, I’ll send him (via my mother) an interesting news article or blog post which he has my mother print out for him.

My brother and I have noted that he felt a little left behind with the whole “internet thing”, but that he was not comfortable using traditional computer interfaces or looking at high-glare screens…that and he didn’t like sitting at a computer.  But he does like the content that’s available on the internet. He’d just like it filtered for his needs with a minimum of fuss.

I’ve been watching how the Kindle technology has been developing. Reviews that I’d read of the original Kindle kind of left me with the impression that it “wasn’t quite ready for prime time”. Definitely not right for Dad. The new Kindle 2 seems to have addressed a lot of the concerns I had. For those that are interested, here are the new specs:

Say Hello to The New Kindle
Slim: Just over 1/3 of an inch, as thin as most magazines

Lightweight: At 10.2 ounces, lighter than a typical paperback

Wireless: 3G wireless lets you download books right from your Kindle, anytime, anywhere; no monthly fees, service plans, or hunting for Wi-Fi hotspots

Books in Under 60 Seconds: Get books delivered in less than 60 seconds; no PC required

Improved Display: Reads like real paper; now boasts 16 shades of gray for clear text and even crisper images

Longer Battery Life: 25% longer battery life; read for days without recharging

More Storage: Take your library with you; holds over 1,500 books

Faster Page Turns: 20% faster page turns

Read-to-Me: With the new Text-to-Speech feature, Kindle can read every book, blog, magazine, and newspaper out loud to you

Large Selection: Over 230,000 books plus U.S. and international newspapers, magazines, and blogs available

Low Book Prices: New York Times Best Sellers and New Releases $9.99, unless marked otherwise

In addition to the  features advertised above, the new Kindle will enable my Dad to view email and have access to the content on the internet that he’ll actually use. There are a lot of  hacks to the Kindle that I will explore for about a month before giving the device to my Dad and then teach the ones to him that he’ll use/like.

Now, this is not a tech blog.  So why am I  going on about the latest gadget? Well, it is my prediction that technology like the Kindle, the iPhone, and the like which make technology feel less like technology will have a huge impact on the medical industry, both in research and in general practice. Many physicians are like my Dad; they’ve specialists who have focused on things *other* than what many of us have started to think of as “standard technology”.  I attended a conference (a little over a year ago) that was looking at the merging technological needs of both general practice and research. At this conference (put on by ExL Pharma), the representative from Microsoft (Les Jordan) showed this movie from Steve Ballmer’s key note. If you skip to minute 16:25, there’s a (four minute) peek at Microsofts vision of the future of technology in healthcare. The technology displayed in that clip essentially is in existence today. We’re just in the development-adoption lag. It will be interesting to see how some of these things work their way into healthcare.

For now, I’m just anxiously awaiting the new Kindle.

~TJK

The glass is half full/empty?

As a QA professional I scrutinize the systems, processes, and results (data) of my client groups (the operational areas….i.e., the people who do the real work). This can be very frustrating for people; especially those who work hard, do good work, and aren’t used to having someone doubt them or subject them to the third degree….physicians often have a particularly difficult time with this.

I understand this and strive to make my intrusion on their daily work as unobtrusive as possible. I also try to explain to them exactly what my thought processes are and the rationale for my questions. One of the things I like to tell my client groups/auditees is that I am an optimist who’s paid to be a pessimist. That’s simple and to the point and it seems to convey my position to my client groups/auditees rather well.

More accurately, I’m an optimist who’s paid to be the exact right combination of the guy who sees the glass half full, the glass half empty, and the cracks in the glass. They pay me to see the good, the bad, and the ugly; to take a good system and try and break it…..just to see if someone can.

Below, I’ve assembled a few (real) scenarios that I think illustrate my role:

1) In this case, I was auditing at a Clinical Investigators site (a doctor’s office). At one point in our exit interview he felt that I (a non-physician) was questioning his medical opinion. To which I told him, “I would never question your medical opionion; I’m not qualified…..but based on your source notes, I can’t tell what your medical opinion was….or even that you had one”. Understanding stole across his face…..Documentation. That’s what was missing. He was doing the work in a stellar fashion,  but not documenting it sufficiently.

2) Another physician was less convinced of the need to explicitly document his diagnosis. “Any clinician would immediately have the same diagnosis…its self-evident!”. Again as a non-physician, I told him that I was sure he was right, but that FDA would likely send a “non-clinician”; someone who would look at his documentation in a manner more akin to that of an attorney than of a medical professional….”Oh, I think I understand what you’re telling me now.”

3) A third physician tried to correct me on calling study participants “subjects” rather than “patients”….”subject sounds so cold and uninvolved”. To this, I explained my position that a “patient” is someone who comes to a doctor looking for something tried and true to make them better. A study “subject” is someone who is taking a gamble out of philanthropy, desperation, or a combination of both….someone that, with their informed consent, we are putting in some measure in harms way. They deserve our highest respect and greatest level of care. Patients are very important; study Subjects are doubly so. This doctor seemed a little irritated at my little philosophical tirade (short though it was), but he seemed to understand the point I was making…I guess he thought I was an idealist of some sort…

4) While meeting with a team that was conducting validation testing on  a clinical computer system, some on the team were frustrated by the level of testing that I was recommending (requiring?). “Well in an ideal world, we would test everything…..”….I had to correct him, “In an ideal world, software testing wouldn’t be necessary because everything would work right out of the box in a perfect and unqualified way…We test our software to ensure that it is actually working like we think it is”. He didn’t like that response, but at least he was quiet”.

Are there any others with anecdotes or questions relating to GxP?

~TJK

Ignorance on the Placebo Effect

I was reading some blog posts over at Wellsphere when I saw the following thoughts on the placebo effect from Seth Roberts

What Should Double-Blind Placebo-Controlled Trials Be Replaced With?

For a sick person, which is worse?

1. Getting better for the wrong reason.

2. Wasting a lot of money.

It sounds like a joke — #1 isn’t even harmful, whereas the cost of health care is a very serious problem. Yet the FDA and legislators with FDA oversight have been given this choice — and chosen #1. They have chosen to protect us against #1 but not #2.

If you get better from a placebo effect, that’s the wrong reason. How dare you! The requirement that drugs be better than placebo controls prevents this from happening. The requirement might have been — but isn’t — that a new drug be better than pre-existing alternatives. Many aren’t but they are always more expensive — not to mention more risky.

Now Seth has a Ph.D. in psychology, blogs on science-related topics, and seems like a smart enough guy, but his post is a bit misguided.

1) The reason that drugs are required to perform better than a placebo is because the placebo effect tends to only occur in a small set of patients. That is that the mental makeup of a specific patient is the cause of a placebo response (irregardless of the treatment). It is also not clear whether a placebo respondee is “actually getting better”. It is just as likely that they were not actually sick in the first place (or as sick as they thought).

2) Those patients who are not predisposed toward exhibiting placebo responses need to be given an actual effective treatment to “get better” and therefore deserve medications that exhibit “better than placebo” characteristics. Giving such a sick patient a sham treatment (rather than one that can actually work) can be very harmful in that the person’s condition can actually worsen.

3) There is a requirement from FDA (and regulatory agencies worldwide) that new drugs be as good or better than existing medications; or that they provide some sort of unique benefit (or reduced risk).

4) The expense of new medications is largely due to the high cost of research to make those medications (and fund future research). The low-hanging fruit is largely gone.

Best,

TJK

SQA Abstract – Clinical eData

I’ve submitted an abstract for the Society of Quality Assurance conference this April (right at the Oct 14th deadline). I should hear back by the end of November. I’m not sure if it will be accepted as a full session or as a single presentation (or at all really), but I’m pretty excited about it. I’ll be giving a similar presentation internally at Celgene as part of ongoing training that our group provides, so a lot of the work for it is already done.

The Impact of Electronic Systems and eData on Clinical Research

Abstract
Although the use of electronic data in the pharmaceutical industry is by no means a new phenomenon, its impact has evolved over time. Technology has revolutionized our lives in many ways; in the way we access information, in our entertainment, in the way we do business, and in the way we interact. This technological revolution has had very pronounced impacts on the GxP industries: eRecords, eData, eSignatures, Data Processing, Data Mining and the Regulatory Standards associated with them.

These impacts have been most apparent in the cGMP and GLP areas and there is a fair level of comfort with eData and Validation in those areas. Increasingly however, the impact of eData and the need for controls around its use can be seen in the GCP area. Due to its large reliance on external sources of data, Clinical Research has some unique challenges. This session will cover:

I. Technology in Pharma and Validation Overview: a discussion of these concepts (which are widely felt to be cGMP artifacts) and relating them to the GCP area through analogies.

II. Centralized GCP Technology: The use of centralized eData and eSystems, primarily on the “sponsor side” has some unique challenges due to very short timelines and the external nature of clinical data inputs. Also the challenges of study-specific validation activities will be addressed

III. De-Centralized GCP Technology – “Technology at the Clinic”: Source data at clinical sites varies widely in format, from purely paper systems through purely electronic integrated source systems. However, a large and growing number of sites use a hybrid paper/electronic model with various sources of data, scans of source destroyed by hospital systems, paper notes, dictated notes, email notifications, and central sponsor data collection systems. Some ideas on how to address various hybrid source data scenarios will be presented.

~TJK

Wellsphere Affiliation

I was recently invited by Dr. Geoffrey Rutledge to join the Wellsphere Blogging Community. This was quite a surprise and I was quite flattered.

That being said I wasn’t really sure how I’d fit in at Wellsphere. GxP Zone is a bit of an odd-ball in that community, but I suppose GxP Zone would be a little odd in any blogging community…I really don’t know of any other blog that examines the same sorts of topics in quite the same way. I emailed Geoff and he apparently really liked the post I wrote on ALCOA. In any case, after emailing a bit with Geoff, I’ve decided to join and am excited about the affiliation. Thanks very much.

T. J Kuhn General Medicine

Best,

TJK

Quality – Pirsig says it exists

Zen and the Art of Motorcycle Maintenance

In the car during my commute to work, I’ve been listening to one of my favorite books (on CD), Zen and the Art of Motorcycle Maintenance, by Robert M. Pirsig. Pirsig, who is arguably the world’s most-read, living philosopher argues through a masterpiece of logic and narrative the following:

1) Quality is real

2) We know what Quality is; not from any cognitive, dualistic, subject-object type of knowing, but rather from pre-cognitive knowing.

3) It is natural to put Quality into the things that we do….it is reality (all that Zen stuff).

He says these things in a very accessible way (especially in recorded form) that makes these concepts very personal and accessible. Whether you agree with everything he says or not is immaterial…they are worth thinking about and considering.

Anyway, I’m alone, tired, over-seas…..and I need to get up to go to the airport super- early. I’ll write more about this soon. It is excellent for any and all to read….especially those who must consider Quality as a concept. Jeeze, I’m jetlagged. Good night all,

~TJK

Geeky Pharma Plates

I’m not much for vanity decorations on cars. License Plates, Bumper Stickers, Decals, whatever, they usually just annoy me. I don’t really care to know about the political leanings, sports affiliations, or group memberships of my fellow drivers….save through good conversation. I do so love good conversation. So when I am subjected to reading about these things, billboard style, on the back of their cars as I drive to wherever, I’m more prone to be annoyed than amused.

All that being said, I have noticed a recent trend on these car adornments to embrace the rather geeky technical aspects of the Pharma industry. For example, the other day while driving with my wife, we spotted a car sporting Pennsylvania plates with the ID number “21CFR11″. Now for those of you out of the know, 21 CFR part 11 is the US regulation governing the use of electronic records and electronic signatures in FDA-regulated functions (like drug development or manufacture). I can’t think of a Geekier thing to put on one’s car…I mean, that probably tops “I love Linux” as a mantra.

Another plate I saw a while back, this time from New Jersey, read “PHASE4″. That plate was a co-worker’s at a previous employer. Again, for those out of the know,  with Phase 4 referring to studies performed for a possible new indication (use) for an already approved drug. Again, pretty geeky.

Living in NJ as I do with its high concentration of Pharma companies, I suppose it was just a matter of time. Now, I am interested in both Phase 4 and especially 21 CFR part 11, but I think I’ll keep that off my car.

For those interested in these topics, I’ve pulled the following information from the FDA website for your reference:

Phases of an Investigation

An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. The three phases of an investigation are as follows:

Phase 1 includes the initial introduction of an investigational new drug into humans. These studies are usually conducted in healthy volunteer subjects. These studies are designed to determine the metabolic and pharmacological actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. Phase 1 studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. The total number of subjects included in Phase 1 studies is generally in the range of twenty to eighty.

Phase 2 includes the early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase 2 studies usually involve several hundred people.

Phase 3 studies are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Phase 3 studies usually include several hundred to several thousand people.

and

this slide presentation from the 2002 DIA that summarizes Part 11.

~TJK