Monday, May 30, 2011

Differences between SOPs and WPs

Working in industry setting (versus academic), we all understand that it is critical for us to be familiar with the Standard Operating Procedures (SOPs) / Working Procedures (WPs) and follow these procedures. This is even more obvious in pharmaceutical and drug development industry. An employee could be fired not because of incompetence, but because of violating these procedures. A couple of days ago, I attended ChineseAssociation for Science and Technology Annual Convention, one session was to discuss about the requirements for starting up a new company. Several local entrepreneurs elaborated the intellectual property (IP), business plan, funding, a loyalty team, and so on. Nobody mentioned these procedures. But I think that it is equally important to have a set of necessary SOPs and WPs in order to start a new company, especially a service-type company in highly regulated drug development field such as contract research organization. Scientists working in the academic setting often find the difficulties when they try to land a position in industry mainly because they lack the ‘industry experience’ – one critical part is that they lack the experience in following up the strict industry SOPs. If you interview a candidate who does not even understand the term ‘SOP’, you know that your candidate will have a long way to adapt to the industry setting. 

While there are definitions for Standard Operating Procedures (SOPs), it is hard to define Working Procedures (WPs), not to mention the differences between SOP and WP.

Standard Operating Procedure is established procedure to be followed in carrying out a given operation or in a given situation. In clinical trial setting, the SOP is defined in ICH E6 as “detailed, written instructions to achieve uniformity of the performance of a specific function. “  SOP is one of the components of a Quality Management System (QMS) implemented in many large organizations - improve quality by providing a standard format, approach, and application of common processes.. 

The issue may be with the wording ‘detailed’ in this definition. The common understanding within the industry is that SOP needs to be written in a little bit high level and the working procedure provides the detailed steps according to SOP. If the strict definition of SOP from ICH E6 is followed, there perhaps should not be any working procedures. All working procedures should be called SOPs. There is really no defined boundary for separate the SOPs and WPs. For SOPs, say what you do... but do what you say. The documentation is always important to the SOP compliance. 

My personal opinion is that SOPs are the procedures we must follow, typically on high level, with GCP compliance while WPs are procedures we should follow, typically in more detail, for internal standardization and efficiency. For example, in biostatistics, a SOP must be in place to require the independent validation for statistical outputs. A WP may be created to detail how independent validation should be implemented.

Here are some observations about SOPs and WPs:

1) Within FDA, the term SOPP (standard operating procedure and policies) is used for SOPs and WPs.

 2) There are two papers containing good discussions about SOP:
 3) There seems to be no formal definition ‘working procedure’. Different companies may call this differently and different people may have different understanding for ‘working procedure’.
There are some discussions on the web: 

Having SOPs and WPs in place is one thing; having everybody trained on SOPs and WPs is another thing. If SOPs and WPs are written in great detail like step-by-step instructions, the procedures may become a burden to be followed. This could in turn cause issues in SOP compliance when there is an audit. 

Last week, we had a group meeting during the lunch time and we ordered some food from Jason’s Deli. It was good to see that the delivery guy brought a Bagset Checklist which listed the items and quantities for each item. Unfortunately, the guy clearly did not follow their procedure and did not check the check list. When he delivered, he realized that he forgot to bring ‘bulk chips’. He had to go back to pick up this missed item. Had he follow the procedure and check his Bagset Checklist, he would have not missed any item. In this case, the consequence of the non-compliance is minor, but in clinical trials, the consequence of the non-compliance could sometimes be very significant.

Saturday, May 14, 2011

I-Spy 2 Trial - a study with fancy name and fancy design

If you see the term “I-spy”, you would typically think something related to movie, kids game or TV series. Recently, I-spy has been linked to a novice clinical trial design in breast cancer.

For a short description about this study, is a good place. In, I-SPY 2 TRIAL is listed as “Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer”. For more detail descriptions about this study, you should check out the following websites:
This study got a lot of publicities. For example, in FDA’s ‘advancing Regulatory Science for Public Health’, it specifically mentioned the I-Spy 2 trial,

Personalized treatment for cancer

The “I-SPY 2 TRIAL,” launched in March 2010, represents a groundbreaking new clinical trial model that will help scientists quickly and efficiently test the most promising drugs in development for women with higher risk, rapidly growing breast cancers. During the trial, drugs in development are individually targeted to the biology of each woman’s tumor using specific genetic or biologi­cal markers, known as “biomarkers.” By applying an innovative trial design, researchers will use data from one set of patients’ treatments to treat other patients – more quickly eliminating inef­fective treatments and drugs. The I-SPY 2 trial was developed under the Biomarkers Consortium, a unique public-private partnership that includes the FDA, the National Institutes of Health, and major pharmaceutical companies, led by the Foundation for the National Institutes of Health
. “

The claimed advantages for this trial design are:
  • Utilized Personalized Medicine
  • Uses genetic or biological marker (“biomarkers”) from individual patients’ tumors to screen promising new treatments, identifying which treatments are most effective in specific types of patients
  • Improved Efficiency (fewer patients, less time, and fewer resources)
Enable researchers to use early data from one set of patients to guide decisions about which treatments might be more useful for patients later in the trial, and eliminate ineffective treatments more quickly Enable the development of more informed, smaller phase III trials

So what is this trial design? Can this trial really achieve its purpose? Here is what I would say:

  • I-Spy 2 is a phase II study, anything generated from this study will need to be confirmed in Phase III confirmatory studies.
  • I-Spy 2 is a government-sponsored study and supported by Foundation of NIH, Biomarkers Consortium, NCI, and others. It may never happen if it is an industry-sponsored study.
  • I-Spy 2 is academic study and not a study for product licensure. If it is study for product licensure, there may be difficulties for study design to be accepted by regulatory agencies.

  • I-Spy 2 design is complicated and it employs Bayesian Adaptive, Response Adaptive Randomization (play-the-winner approach), Biomarker Adaptive, Stopping and adding treatment arms. The algorithm and stopping rules are complicated and the assumptions / basis for generating these algorithms / stopping rules may eventually be demonstrated incorrect. 
  • I-Spy 2 is a randomized, open label study. It would be more difficult to implement if this is a double-blinded study
  • I-Spy 2 got it fame due to its use of ‘personalized medicine’, ‘adaptive design’ – all fit into the hot areas
  • I-Spy 2 is a multi-center, NOT multi-national study. It would be much more challenging if this is a multi-national study
Although I-Spy 2 got a lot of attentions, not everyone is convinced with this design. The study is closed watched – let’s see the fate once it is completed.