FDA IP Labeling Requirements

April 29, 2012

FDA labeling investigational product

Does FDA Require an Expiration Date for IP?

What are FDA’s requirements for labeling investigational drug and biological products (IP)? We are all aware of the required statement in 21 CFR 312.6, “(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement ‘Caution: New Drug–Limited by Federal (or United States) law to investigational use.'” However, is that the only requirement? What else, if anything, belongs? What labeling is against FDA requirements? Is this a GCP or GMP issue? This question came up recently in a discussion with a colleague. It was their opinion that an expiry date was not required. They had stability records for the IP and could show that the expiration date exceeded the length of the trial. Is this sufficient? I disagreed. I felt that the IP labeling should include a lot/batch number and the expiry date.

What Are YOUR Viewpoints? Please comment below.

FDA regulations for investigational new drugs tell us little about what goes on to an IP label. However, we know that IP must be manufactured under the GMPs. Just what do the GMP regulations say about labels? We can find it in § 211.137, Expiration Dating. It states in 211.137(g):

“(g) New drug products for investigational use are exempt from the requirements of this section, provided that they meet appropriate standards or specifications as demonstrated by stability studies during their use in clinical investigations. Where new drug products for investigational use are to be reconstituted at the time of dispensing, their labeling shall bear expiration information for the reconstituted drug product.”

FDA Drug Labels

Consultant's Don't Enjoy Being Wrong

It is clear that my colleague is correct. FDA does not require expiration dates if the IP meets the standards and/or specifications in stability studies. I don’t like making mistakes, but “the proof is in the pudding.” This is a very specific regulation that is easy for all of us to interpret. I would have appreciated it if FDA had referenced this in the IND regulation, §312. That is where most GCP professionals go to look for FDA’s GCP requirements. However, FDA frequently doesn’t appreciate what I appreciate, so we find the information in §211.

The second point that this regulation makes is very interesting. More and more drug products require very specific instructions on how to administer the drug or IP. A reconstituted test article can have a very short time period for dispensing. This regulation is equally clear that “their labeling shall bear expiration information for the reconstituted drug product.”

This can add up to a lot of information. Expiration information for a reconstituted drug product, storage temperatures and conditions, and adequate directions for dispensing the IP are all essential information for a label. How in the world do you fit it on one small container? For this, you need to understand FDA’s definition of “label.”

In conducting your clinical research program your ultimate goal is to attain a “label.” This is the physician’s insert that informs the clinician, among many other things, “adequate instructions for use.” Vials of parenterals are usually packaged and the packaging contains essential information that is also considered labeling.

FDA investigational product labeling

FDA Labels Must Not be Misleading

In addition, the handy “informational sheets” that some nutritional supplement or “neutraceutical” dealers keep under the counter at their stores and are given out to answer question from consumers also meet FDA’s definition of labeling. So when they hand you an informational brochure saying that “many studies find” that patchouli oil cures arthritis, yes that can be part of the label. Chances are that FDA would probably find it to be false and misleading.

That means you should have plenty of room for this information on the IP labeling. Referencing it on protocol-specific worksheets that the clinical site may, or may not, use for recording source data is not sufficient. The information needs to be part of the labeling or clearly stated in the protocol. It can also be part of pharmacy manual that is referenced in the protocol. The information needs to be readily available and part of the pre-study training that the sponsor documents before enrollment of subjects.

FDA Labeling

European Requirements

Finally, a European employee of the company my colleague works at informed me that it is an EMA requirement to include the expiry date. However, she had heard that in the U.S. there was no requirement, which she found strange. I find it strange as well. It is my viewpoint that in an era of globalized trials, we should aim for the highest standard. And harmonizing label requirements, when possible, will help the company develop a systematic approach to GCP compliance.

My personal opinion is that expiration dating is essential information for “adequate directions for use,” as required by Section 502 of the FD&C Act. I agree with EMA that the expiry date should be part of the label. However, I live in Tacoma, WA, not in Paris, Copenhagen, or Venice. So my personal opinion is just that, my personal opinion.

Carl Anderson, GxP Perspectives

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Quantifying Quality for GxP Compliance

April 8, 2012

quantifying quality GxP

Quantifying Quality

GxP professionals understand the need for quality and quality system and we discuss quality with one another on a daily basis. But how do we measure it? How do we quantify our results? Once again we turn to Len Grunbaum and Emma Barsky, regular contributors to GxP Perspectives, for their insight on how to quantify quality for the development manufacture, and distribution of health products such as drugs, medical devices, and biologics.

Quantifying Quality

In its simplest form, the definition of “quality” is “how good something is.” But what exactly does this mean for the life science industry, whose frame of reference is defined by regulations which are often vague and which provide little or no guidance regarding how they should be implemented?

In light of this, we would like to offer some ideas regarding how to measure – quantify – how good your “quality” is in tangible and practical terms. We contend that such metrics are useful in order for company management to make sound decisions regarding whether and/or where the quality system (i.e., the operational infrastructure that promotes and facilitates “quality”) requires improvement. The following key indicators are not all-inclusive (nor are the items mutually exclusive), but they provide meaningful ways to assess your “quality”:

• Number of successful external and internal audits as a percentage of the total number of external and internal audits: the higher the percentage of successful external audits (e.g., by existing/potential clients, regulators), especially when you have a large number of them, the better your “quality.” Passing one audit with flying colors is great but passing multiple audits with few minor or no observations is way better. It not only sets a trend regarding “legitimate” quality but it also validates the company’s degree of quality from different perspectives. This scenario allows any company to claim that its quality system has withstood scrutiny from a variety of companies and/or regulatory agencies over a long period of time.

While “looking good” to the outsiders is great, “feeling good” about what is under the covers is even better. Therefore, if thorough internal audits do not find any issues that either directly (critical observation) or indirectly (major observation) impact subject/consumer safety and/or data/product integrity, then “quality” is inherent to the operations.

GxP quality quantify

Measurements for Success

You may wonder how a subjective term like “success” is defined in this context. Fair question. A result of “no audit findings” (e.g., no FDA 483s, no audit observations) is the clearest measure of success. A relative handful of “minor/cosmetic” issues is not perfect but is certainly acceptable in this context. To the extent that the number of observations may be “critical” or “major,” as defined above, the audit will certainly be viewed as less successful or even unsuccessful. One should also remember that it is a common thing in the industry to consider a large number of minor observations as a major issue because this scenario gives an impression of a negative trend, the latter of which is not conducive to having quality operations.

Number of “directed” (i.e., “for cause”) audits as a percentage of total audits: because directed audits are performed to follow up on actual or perceived regulatory compliance problems, the higher the number of “directed” audits, the more questions will be raised about your “quality.” “Directed” audits could be external (i.e., performed by existing clients or regulatory authorities) or internal (i.e., performed by internal quality staff). The higher the number of problems confirmed, the weaker the quality system. Even if these types of audits indicate in general that there are no actual problems, or a minimal number of problems, a large number of such audits should prompt questions regarding why the perception exists that the degree of “quality” is such that an investigation is required.

quality

Number of Investigations

Number of investigations/CAPAs: an investigation is a formal and documented process performed to gather information (e.g., root cause, impact) regarding a specific problem encountered (e.g., a customer complaint, a missing controlled document) and which, depending on the outcome of the investigation, may lead to corrective and preventive actions. An “excessive” number (the definition of which is admittedly subjective in nature) of investigations, even if satisfactorily completed and closed, gives an impression that the underlying cause has never been properly identified and/or corrected.

Number of repeating issues as a percentage of the number of audits performed: repeating issues are symptomatic of a quality system that does not correct or otherwise effectively address problems. While isolated incidents are not necessarily a reflection on the company’s overall quality, incidents that span multiple project teams and/or departments and/or are observed more than once may be indicative of quality-related problems. It is very difficult to convince anyone of the quality of operations when problems that are systemic in nature become evident.

The higher the percentage of audits that contain repeating issues, the more likely that this may be viewed as 1) management indifference, 2) lack of management involvement, 3) inappropriateness of personnel qualifications and/or 4) inability/unwillingness to invest in “quality.”

quantify quality GxP

Lost Business

Number of business opportunities lost due to unsuccessful external audits as a percentage of the number of external audits: audits are sometimes performed as a basis for determining whether a business relationship should be consummated or continued (e.g., you will be chosen as a vendor/supplier, an existing relationship will be sustained) or expanded (e.g., a company will be awarded additional projects). Some life science companies (e.g. pharma, biotech) have to get clearance from the FDA prior to being able to market their product. Support companies (e.g., CROs, contract manufacturers) may have to undergo due diligence inspections to establish/maintain/enhance a business relationship. The higher the percentage of such opportunities lost (e.g., loss of a potential or existing client, project cancelled/not awarded, FDA did not grant an approval) because of poor audit results, as a percentage of external audits performed, the stronger the indication that your “quality” is dangerously weak. This, in turn, has a financial “bottom line” impact on the company: loss of business opportunities can also be translated into wasted R&D cost and/or lost anticipated revenue, both of which become a major risk to the company’s financial health.

In addition to the items listed above, there is another important quantifiable component to “quality,” which is too often being overlooked or not being considered at all. This component is what we define as “the monetary expenditure associated with ‘quality.’” Namely, we are talking about an operationally quantifiable parameter – cost of establishing and maintaining “quality” operations. Most will argue that “quality” is very expensive no matter what. We firmly believe that it does not have to be that way if the underlying causes, which directly and unnecessarily contribute to the extra cost of doing business, are either eliminated or minimized. Here are a few examples to give you a flavor of what can contribute to increased costs when it comes to meeting the regulatory responsibility of instituting and sustaining “quality”:

Regulatory compliance decisions that are not defined in writing and/or are not defensible.

Cumbersome and inflexible procedures that require more resources than necessary to execute them without “procedural deviations.”

Inefficient procedures that require the same activity to be done more than once in order to be in compliance.

Ineffective procedures that do not reach the desired objective of being in compliance after the first execution.

Unclear procedures that result in too many on-going corrections in order to inject “quality” into operations.

Too many procedures that company staff must follow without any value added.

Contradictory procedures that lead to generating Notes-To-File, CAPAs, deviations, investigations, etc. because compliance to one procedure results in non-compliance with one or more other procedures.

GxP Quality

The Costs and Benefits of Quality

The above-listed activities not only translate into the need to spend more time and money in an attempt to have operational quality, but a number of these items translate into further quality-related costs to the company. Examples of the latter include, but are not necessarily limited to, taking the time to respond to observations or even worse yet, an FDA-483 or a Warning Letter. We think the point we are trying to make is clear…

Our bottom line is that you can make both your QA and CFO happy by quantifying “quality” in terms that will be understood and appreciated by both. This means that sound decisions can be made regarding whether and/or where to apply precious company time and resources help ensure that your “quality” is as good as it can be without putting the business out of business.

Emma Barsky and Len Grunbaum
Partners of The Practical Solutions Group, LLC
609.683.0756
Practical Solutions

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In News from FDA: Yet another weight loss danger in Japanese “rapid weight loss” pills. Read the story: foodconsumer.org

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FDA & Politics: In the Interest of Science?

April 3, 2012

FDA and politics

Political Pressure at FDA?

FDA Regulates 25% of the U.S. economy and has long been the target of lobbyists from the food,drug, & tobacco industries.The question is always asked: “Is mixing the public health mission of FDA with politics in the current political climate advancing the interests of the American consumer?” Unfortunately, the answer is almost always no. Last December GxP Perspectives published a Guest Commentary on “when Politics and Science Collide,” by April Mayberry. In the 03 April 2012 New York Times there is an extensive page one article on the differences between the Obama White House and FDA on public health issues.

For most readers of this blog it is a question on the approval of health products; drugs, medical devices, and biologics, that come to mind. Is FDA providing the right balance in regulatory oversight? Is FDA making decisions based on science and not political pressure? The issue came to a head over the Plan B controversy that April Mayberry wrote about in her Guest Commentary. In this week’s FDA Matters, longtime FDA observer Steven Grossman talks about different plans to speed up FDA approvals noting that there are rarely initiatives to make sure that FDA scientists have the time and resources to make the right decisions. Grossman notes that former FDA Commissioner Dr. Andrew Von Eschenbach wrote an opinion piece in the Wall Street Journal where he states:

FDA and Politics

Dr. Andrew Von Eschenbach

What will it take to realize the potential of the new medicine? The United States has the world’s most innovative drug and device companies and research universities, plus the unparalleled National Institutes of Health. What’s missing is a modernized Food and Drug Administration that can rapidly and efficiently bring new discoveries to patients.”

This places the burden, and blame, for new health product approvals squarely on FDA. The New York Times article points out that political pressure has often shaped FDA policy and that there have often been serious consequnces when FDA tries to assert its independence. For example, FDA Commissioner Dr. Jane Henney lost her job for allowing the approval of the controversial drug RU-486. Although then DHHS Secretary Donna Shalala guaranteed Dr. Henney that FDA would have independence to make scientific decisions, she was soon out of a job with the election of George W. Bush.

FDA and politics

Dr. Margaret Hamburg has Supported FDA Scientists on Plan B

Current FDA Commissioner, Dr. Margaret Hamburg has not had as supportive a relationship with the current DHHS Secretary, Kathleen Sebelius. They clashed on the restrictive measures insisted on by Secretary Sebelius for access to Plan B. Other areas of disagreement include labels on sunscreens and over the asthma drug Primatene Mist. In an election year the volatile mix of politics and science is even more apparent. In the New York Times article FDA historian Daniel Carpenter of Harvard University warns:

In a globalized world , where trust is a huge part of what American manufacturers have to sell, the politicalization of the FDA’s reputation could hurt not only consumer protection but industry profits as well.”

It should be an interesting year for science and politics.

Carl Anderson, GxP Perspectives

Read the New York Times Article

FDA Matters

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Drug Accountability in Clinical Trials

January 19, 2012

clinical trials study drugs

Drug Accountability in Clinical Trials

Drug Accountability Is the one thing that everyone looks at and everyone ignores in clinical trials. I don’t know how many times I have read in a monitor’s report that “drug accountability not done due to time restraints.” Yet consistently “test article accountability” (as FDA refers to it) is one of the top findings on a Form FDA 483, Inspectional Observations, issued for clinical trials. In this Guest Commentary pharmacist Roberta Wong outlines the basics for clinical trial professionals. She concludes with six issues for clinical trial sites to consider. She is a consultant to biopharmaceutical companies and teaches at the Pharmaceutical BioEngineering Program at the University of Washington.

Guest Commentary by Roberta Wong, PharmD

Drug Accountability in Clinical Trials

It’s not exciting, it’s not cutting edge. It may be the last thing you think about when preparing for an FDA audit. You might scan the records and figure if all the lines are filled in, it must be okay. Or, the auditor might not look at it, so I will trust that the pharmacist did it correctly. After all, aren’t pharmacists one of the most trusted professions? Consider this: if drug accountability is in question, then the whole study could be in jeopardy. Proving that the drug was administered to the patient that resulted in the effects seen from study drug is a key factor in determining the merit of a product candidate. The FDA has listed drug accountability as #3 in a list of top 5 pitfalls.

drug accountability in clinical trials

What FDA Considers

The FDA uses these categories for determining the seriousness of a deficiency. Sometimes, minor sloppiness is due to poor record keeping. This can be corrected with training, and close follow-up to insure consistency amongst staff. Sloppiness, if bad enough, can cause removal of data from study results, impacting the overall quality of the data, and the integrity of the study conduct. Often unintentional, lack of attention to detail, and not understanding the importance of accurate recordkeeping in the drug application can contribute to a clinical trial site’s data being thrown out of a sponsor’s application. Training staff at the study initiation visit and checking the quality of the work during the course of the study is critical for good record keeping to be maintained during the clinical trial. Staff can change, so retraining may be needed as new staff members are added to an ongoing study.

drug accountability in clinical trials

Intent to Deceive?

On the other hand, some inconsistencies in drug accountability can be due to a true intent to deceive. Drug supplies that are listed as destroyed, lost, or dropped, can be traced to individuals diverting supplies for themselves, or with the intent on selling study drug to other individuals. Investigational drugs can also be switched in an attempt to give drug preferentially to certain patients, if there is also a placebo as part of the study. Limiting access to investigational drugs is a key role for the pharmacist in studies conducted at large institutions. At smaller sites, or individual physician’s offices, study drug may be held by research or nursing staff. In these situations, limiting access and providing locked security for study drugs is required by the study sponsor.

So, what happens when a clinical trial site has drug accountability problems? If this occurs during a clinical trial, the Sponsor will stop new drug shipments, and may suspend study enrollment temporarily. Visits to the site by the sponsor will ascertain the cause of the problem, and determine if re-training will prevent future issues. During this investigation, reviewing the records with the study coordinator and the prinicipal investigator are imperative. And of course, documentation of any meetings with site staff summarizing the corrective action is essential. Ongoing audits for the remainder of the trial will demonstrate that the interventions were successful, and the site is now compliant in maintaining accurate drug accountability.

drug accountability in clinical trials

"Shooting the Dice" with Your Clinical Trial?

Drug accountability is more than just counting pills and vials. Site staff must insure that the study subject receives the study drug, and receives the correct dosage. There should be documentation to support drug administration. If the patient self-administers study drug, often diaries and pill vials are collected to validate the administration of study drug. If the drug is administered at a clinic visit, there are often forms to complete to verify the dosage that was given to a study subject.

How can you avoid problems with drug accountability? First, make sure that all involved in the study are consistent with their documentation. Make sure that the records are completed with the drug dose, patient, date, time and individual removing drug from the central inventory. If study drug is administered in the clinic, the worksheet should note the date, and actual time that the drug was given. If drug is not administered, even though a dose was prepared, then a note should record that drug was destroyed. If study drugs require refrigeration, then the accountability records should have a place to note the temperature.

Lastly, issues with accountability need to be addressed quickly and a solution determined. Vigilance in accurate documentation will insure minimal issues. Making sure the patient received the proper dose is one more way to insure that well-run clinical trials produce good quality data.

How do you know if your system is set up to produce good drug accountability? Here are some questions that you can answer about your study.

Questions to consider:

1. Did the patient receive the proper dose? How do you know?

2. Did the Physician calculate the correct dose? Who double checked the calculation? Is it weight-based? Is the dose calculated at study enrollment? Is the dose recalculated based on the patient’s baseline weight or dose the dose change only if the weight changes by 10%?

3. Drug was sent to the clinic to prepare a dose, and the patient was a no show. Should the drug be signed back into the central inventory? (If the drug should be refrigerated, and you are unsure of how the drug was stored, what should you do?)

4. Drug was prepared for a patient who was a no show, but promised to come in the next day. Can you save the prepared dose and administer it the next day?

5. Does your clinical trial allow documentation of these issues in the study records?

6. For study drug accountability, who resolves new issues? Where do you record your answer? How do you train the rest of the staff regarding this issue?

Contact Robbie!

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Commentary on Plan B Controversy

December 28, 2011

Plan B Kathleen Sebelius

Kathleen Sebelius Overturns FDA on Plan B

Plan B is an emergency contraceptive, sometimes called “the morning after pill,” that has been approved as safe and effective for its intended use by the Food and Drug Administration. The drug’s safety is pretty much beyond dispute. However, it is access to Plan B that is proving controversial. In question is whether Plan B can be available over-the-counter or on a prescription basis for all women of child-bearing potential. This includes those under 18 years of age. FDA had said yes. In an unprecedented decision, the Secretary of Health and Human Services, Kathleen Sebelius, overturned a decision by FDA. The decision, in early December, has largely been overlooked by the general public with the onset of the holidays and college football bowl games. However, it has profound implications for millions of Americans and perhaps the way FDA approves drugs in the future. FDA Commissioner Margaret Hamburg issued a public statement after the decision defending FDA’s scientists who had recommended the OTC approval (see below).

The following Guest Commentary by April Mayberry discusses this decision. In it she gives her opinion on the Plan B decision. GxP Perspectives, as always, welcomes your own viewpoints and opinions.

When Politics & Science Collide

Plan B

Plan B Emergency Contraception

As a clinical research professional working in women’s reproductive health and contraceptive development, I was disturbed by Dr. Sebelius’ decision to override the FDA’s decision to allow OTC access to Plan B for girls under 17. First my reaction was concern about the impact this will have on women and contraceptive development. Second was to wonder why Dr. Sebelius, an Obama appointee with a strong reputation for supporting reproductive rights, would make such a decision.

In her statement posted on the HHS website, Sebelius said that Teva didn’t provide sufficient evidence that Plan B could be used safely in very young adolescent girls, or that they could understand the labeling. She said if Teva could produce data to the contrary they could refile. If Sebelius’ decision was intended to protect girls, it doesn’t seem logical.

• An adolescent girl has a much higher chance of serious complications from an unintended pregnancy or an abortion than from Plan B.

• Other potentially dangerous OTCs used, and even abused, by young women have no such restrictions. This includes diet pills, cold medicines, aspirin, ibuprofen and acetaminophen, all of which are associated with serious and/or fatal AEs.

• In my experience, controversial products not indicated to treat immediately life-threatening conditions must meet a particularly high approval standard. In a public statement appearing on the FDA website, FDA Commissioner Margaret Hamburg said:

“The Center for Drug Evaluation and Research (CDER) completed its review of the Plan B One-Step application and laid out its scientific determination. CDER carefully considered whether younger females were able to understand how to use Plan B One-Step. Based on the information submitted to the agency, CDER determined that the product was safe and effective in adolescent females, that adolescent females understood the product was not for routine use, and that the product would not protect them against sexually transmitted diseases. Additionally, the data supported a finding that adolescent females could use Plan B One-Step properly without the intervention of a healthcare provider.” In the same statement Dr. Hamburg contended that:

Dr. Margaret Hamburg, FDA Commissioner

Dr. Margaret Hamburg, FDA Commissioner

“The review process used by CDER to analyze the data applied a risk/benefit assessment consistent with its standard drug review process. Our decision-making reflects a body of scientific findings, input from external scientific advisory committees, and data contained in the application that included studies designed specifically to address the regulatory standards for nonprescription drugs. CDER experts, including obstetrician/gynecologists and pediatricians, reviewed the totality of the data and agreed that it met the regulatory standard for a nonprescription drug and that Plan B One-Step should be approved for all females of child-bearing potential.”

So if FDA used the standard review process why isn’t it enough? Most agree this decision was not based on science. One can only speculate why Sebelius, an Obama appointee, with a strong record regarding women’s reproductive rights, would do this. Possible reasons that come to mind are:

There has been pressure from the religious right on the government against Plan B and contraceptives in general. Plan B is of particular contention, because some mistakenly believe that it terminates pregnancy. Reportedly while governor of Kansas, Sebelius at times modified policy under pressure when it was seen as a political advantage
(also reportedly in these instances the decisions didn’t pose a risk of clinical or other harm to women. In light of reports that she is a subject of backlash by the church.) and of a lawsuit by Belmont Abbey College over the mandate requiring them to provide contraceptive coverage in their health plan, it’s feasible OTC access to Plan B for girls under 18 was sacrificed in lieu of mandates Sebelius considers more crucial, such as requiring health-care plans to provide contraceptive coverage. (Sources: RealityCheck.org, National Catholic Register, and Washington Times)

Plan B access

Should Teenagers Have Access to Plan B?

Regardless of the actual motives behind this move, it has a real potential for negative ramifications. Requiring a young girl to consult an HCP (most having limited office hours) poses potentially insurmountable obstacles to accessing Plan B in the time it’s most effective, possibly resulting in an unintended pregnancy. She must have access to an HCP, know how to navigate the system, have transportation and maybe money. For a young woman who is in a dysfunctional situation or is victim of sexual abuse, these barriers could compound their duress and risk, especially if a pregnancy resulted.

Women over 17 are also affected. Having to present an ID to a pharmacist can cause distress for some. Additionally many pharmacies have limited hours, and in some states some pharmacists may refuse to provide Plan B under the “conscious clause”, all causing delays in accessing it within the optimal treatment window. This is of particular concern for poor women in some rural or inner city communities with few pharmacies and for women with no ID.

Sebelius’ decision may also stifle contraceptive development. According the New York Times this is the first time that the HHS has blocked approval of a product by the FDA. This sets a precedent, allowing approval of contraceptives or other controversial medical products to be blocked without scientifically valid reasons. This is very problematic, because it allows those with political motives to take our national policies and the scientific process hostage to fulfill their own agenda, simply by applying enough political pressure.

April Mayberry, RAC, CCRA, CCRP, CFPHW *

* Certified Family Planning Health Worker

Dr. Hamburg’s Statement on Plan B

Secretary Sebelius’ Statement on Plan B

Pharmacist “Conscious Clause”

NT Times article on Sebelius curtailing availability of Plan B

National Catholic Register Article on Sebelius

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January GCP Training Opportunities:

ExL Pharma has announced that FDA’s Dr. Leslie Ball will give the Keynote Address at the 2nd annual Developing CAPAs in the GCP Environment conference held 19-20 January in Arlington, VA.

GxP Perspectives is a media sponsor.

At the same time and the same place the Trial Master File Summit is taking place with some excellent speakers. Find out more:
TMF Summit Information

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Please comment with your views and opinions!


A Better FDA? Why Not?

December 11, 2011

FDA

A Better FDA?

Is FDA necessary? Most people I know would say yes. We need a strong, independent, effective FDA. Does FDA need improvements? Again, most people I know can point to numerous issues that FDA could handle better. Today, in the Business Section of the New York Times, there is an article on why we need government and the benefits of better government. Yes, the article by Robert H. Frank is about the Tompkins County New York Department of Moter Vehicles, but he outlines some basic principles for better government. Like better use of technology to make government more efficient. FDA is making similar efforts regarding technology. That’s great and I encourage the development. Here are three other areas that I think that FDA can improve:

1. Consistent training for field investigators (CSOs or Consumer Safety Officers). Many times people tell me of an FDA inspection in Salt Lake City that is entirely different from another inspection I have heard of in Tampa, FL. Different CSOs have completely different approaches and conduct the same type of inspection by looking at completely different documents. There are many excellent, experienced CSOs but when different clinical sites or sponsors hear differing viewpoints from CSOs, that isn’t good for compliance or best practices.

2. Changing requirements by review divisions. FDA will tell a sponsor to conduct a study with certain endpoints in order to prove safety and efficacy for their investigational product. Then, as the sponsor is preparing for their application, the rules change. This can cost a sponsor years of frustration and millions of dollars. Yes, safety concerns need to be addressed, but sponsors need to know the rules in advance, and have a reasonable expectation of those rules staying in place.

3. Effective mechanisms for corrective actions. FDA has a Warning Letter close out process. However, it is not evenly applied by different Centers and for different program areas. Regulated industry should have a clear path to performing corrective actions that are meaningful.

So those are my thoughts. I would love to hear yours. Please leave a comment.

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One additional point: My wife, Cathy J. Tashiro, just had her book come out in paperback. No, it has nothing to do with GxPs or clinical trials, she is a sociologist. Her book is:

Standing on Both Feet: Stories of Older Mixed Race Americans

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Read the NY Times article on effective government


An Ethical Question on Medical Oncology Research

October 25, 2011

oncology question

An Ethical Question on Clinical Trials

GxP Perspectives receives some excellent questions and comments about best practices. Here a regular reader asks a very pertinent question on Oncology Research. I don’t have the answer but I am hoping that the GxP Perspectives Community has some people that can help answer this for George. I hope so because I can learn a few things as well. Please comment if you have ideas for George and others to pursue.

An Ethical Question on Medical Oncology Research:

I am not sure the best place to post this question: I work in Medical Oncology Research and I have been noticing what I feel to be a distubing trend in manditory tumor tissue submission. In the past, studies required tissue samples if they were needed to determine eligibility or randomization to a treatment arm (Essentially something that was a potential benefit to the patient or needed to deterimne if study endpoints were met). Those studies usually gave patients the option to allow the sponsor to keep archived tissue for “future testing” that had no benefit to the patient or current study. Recently, some sponsors have been requiring this “archived tissue” as part of the inclusion / exclusion criteria – “If you don’t give us the tissue, you can’t go on our study.” Do you know if anyone is discussing this issue or is concerned how this may impact patient rights?

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Three Comments. The first is from Abby: If the intended use of the archival tissue sample is to send to a central reader to show that the subject indeed has the pathological diagnosis intended for the study, I believe this is a legitimate and important request by the researchers. In the case of a more nebulous use (e.g. “general exploratory pharmacodynamic studies” or “future use”), I do think it is good if the Sponsor can try to provide more specifics, such as “future use in cancer research” or something even better.

It has been my experience that the Informed Consent wording related to these samples must be very clear, and address the short-term and long-term storage of the samples, as well as information on how the subject may revoke that consent and have the samples returned. Clinical sites often request return of the archival samples on behalf of the subject, and sponsors often return the samples–especially if the subject is moving onto another study that also likely requires tissue. Interesting question–and I look forward to hearing other responses!

And the second is from Kevin: As far as the patient’s rights, they aren’t affected at all. As you state, it is clearly in the Inclusion criteria that if you want to participate, the Sponsor requires this sample. This should be included in the consent form as well. The patient, at this point, has the right say “no” to the study.

Sponsors routinely collect these samples as a way to further their research and hopefully capitalize on a novel therapy. I guess you can look at this in one of two ways: 1) Big Pharma is trying to make a dollar (…obviously, which is how/why they exist in the first place) or 2) since they have the ability to take the research beyond the confines of the current protocol, they may just find a cure or improved therapy, which in turn, benefits the patient.

It would be unethical only if the Sponsor took the sample and archived it without the patient’s consent.

My suggestion would to be to discuss your feelings with the Sponsor or to start with, perhaps your IRB.

And Eleanor: There is currently a significant shift in the approach to cancer treatment. In many cancers, there is not a universal response to treatment but some sub-populations respond much more effectively to treatment than the general population. In many cases this response to treatment relates to expression of certain genes by the tumour that do not occur in all patients with the disease. If it is possible to identify the gene and which patients express that gene then treatment is much more effective both in terms of success and in terms of cost.

This may be one of the reasons that sponsors are moving towards mandatory collection of samples. If they identify that a particular sub-population has responded more effectively they can go back and examine stored samples to try and identify the reasons that the sub-population responded more effectively. Thus, there may be the possibility of developing diagnostic tools to identify the sub-population and only treat that population. If there are only limited samples available then it may not be possible to do so. Just a thought…..

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There are THREE Weeks left to comment on the Draft FDA Guidance Document on Risk-based Monitoring
Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring
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How to comment to FDA: Here is a two-slide powerpoint presentation on how to comment on the draft guidance document courtesy of CDRH BIMO. Thanks!

Location of Monitoring guidance FR

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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the Draft FDA Risk-Based Monitoring guidance document and on protocol deviations. There is also a new logo for your viewing pleasure. I invite everyone to join the GxP Perspectives LinkedIn Group and join the discussion.

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