Drug Accountability in Clinical Trials

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.

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.

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.

"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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Clinical Trials in India: An Overview

Clinical Trials in India

India is fast becoming a major center for clinical trials and drug development. The increase in activity has lead the FDA to establish international offices in Mumbai and New Delhi in 2008. FDA states that their mission in India is in part: “… engaging with Indian counterpart regulatory authorities to ensure the timely exchange of information regarding clinical trials that are conducted that support marketing applications in the U.S…” Growing interest in India comes with many questions. What is the history of drug development in India? What type of regulatory structure does India have? What is the infrastructure for clinical trials and drug development? In this Guest Commentary by Jacquie Mardell she gives an overview and discusses some of the benefits, and challenges, of conducting clinical trials in India. GxP Perspectives is fortunate to have a number of readers in India. In fact, after the United States, the country with the most members of the GxP Perspectives LinkedIn group is India. I invite them and others to comment and share their insights about clinical trials in India.

Changes in Indian Clinical Trials Processes Cause for Renewed Enthusiasm

Advanced Clinical Trial Infrastructure

India has become an attractive destination for clinical trials, combining many of the elements western sponsors require: a vibrant urban health care milieu staffed by English speaking professionals with first class medical credentials; an advanced clinical trial infrastructure thanks to the long-standing presence of big pharma companies and major CROs who trained local monitors and project managers in current GCP methodology; the wide availability of high-speed Internet access in offices and hospitals enabling instant remote data capture; and of course relatively easy access to large numbers of willing patients with the conditions western sponsors want to study, such as cardiovascular disease, metabolic diseases such as type 2 diabetes and many types of cancers.

By the early 2000’s, there remained just two significant challenges in conducting Indian clinical trials from the western sponsor’s perspective: shaky intellectual property protection and a long, opaque regulatory process for obtaining clinical trial approval. The former has been resolved by India’s participation as a signatory in WTO’s TRIPS agreement and subsequent harmonizing amendment of her own patent laws in 2005. The approval problem was addressed in late 2006 when India’s regulatory authority, the Drugs Controller General of India (DCGI) and the Central Drugs Standard Control Organization (CDSCO), the Indian regulatory authority, introduced a two track process allowing rapid approval of clinical trials that were part of a global development program.

So we’re all set, right? Sadly, the reality and the promise have not quite met. The DCGI’s office underwent a change at the top shortly after the new approval process was put in place and clinical trial approvals languished for months, against published expectations of 90 days. Despite having well placed regulatory liaisons in New Delhi, CROs can obtain little information to give sponsors, who in turn became disillusioned with the process once again, even with the enticing prospect of all those treatment-naive patients and proven rapid enrollment rates once the trial eventually started.

Harmonization of Indian Regulatory Process

Into this rather frustrating situation has come reason to hope. Recently the CDSCO has signaled an interest in providing more transparency and greater accountability among all parties by releasing several new guidances that harmonize Indian regulatory processes with other clinical trial countries. First, Schedule Y-1 (the Indian counterpart to Title 21 of the Code of Federal Regulations) was amended to require all CROs working in India to register with the authorities to conduct clinical trials (scroll down in the link for English). This requirement has rather more teeth than the FDA’s move in 2009 to require IRB registration, as the authority can reject a CRO’s application.

Secondly, CDSCO this summer published a draft guidance to clarify and streamline the process for obtaining permission to import drugs in small quantities, fewer than 100 doses per patient, for use in clinical trials. This will differentiate from the large quantity application process already in place. Should this draft become a final rule, it would encourage sponsors and CROs to be more precise with their drug calculations on the import license, and to make contingency plans should they wish to expand an existing trial. Despite this apparent additional hurdle, the draft is intended to provide for more uniformity of decision making by the reviewers, and is not expected to change operational policies CROs already have in place.

Finally, CDSCO issued a final guidance on clinical trial inspection procedures effective November 2010, a kind of bioresearch monitoring manual. As with the small quantity test license draft, this guidance provides clear expectations for inspectors and sponsors in preparing for, conducting and reporting an inspection at a clinical trial site or a CRO/sponsor facility, as well as follow up and response actions.

Quest for Quality
Clinical Trial Data

Taken together with the recent introduction of an Indian clinical trials registry listing all clinical trials and sites in India, these changes though incremental, signal CDSCO’s desire to improve oversight of clinical trials and provide clarity for the sponsors and CROs who conduct them. There is even a glimmer of hope that the clinical trial approval process itself might be addressed soon, as October will see a change to the DCGI, India’s top drug official who ultimately approves all applications. Reasonable, reliable approval intervals combined with all the other attractive clinical trial attributes and recent improvements, India is truly an important solution in the quest for high quality clinical data.

Jacquie Mardell
Director/Partner
Anhvita BioPharma Consulting, Inc. (Pvt Ltd)

Please Leave a Comment to Contact Jacquie

Central Drugs Standard Control Organization

India GCP & Clinical Trial Inspection Guidance Documents

Clinical Trials Registry – India

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A comment worth reading from Anusha Reddy Mirayala: “In addition to the above mentioned changes made in Indian clinical trial process.I would like adding the following points

The ministry of health & family welfare, India has constituted a 12 new dug advisory committees to assist the DCGI in the matters related to review and regulatory approval of new drugs and clinical trials (except INDs), chalking a roadmap for proper development of new drugs.

Also the agency has come up with the draft guidance on approval of clinical trials and new drugs in july this year. which will help the industry to submit the required documents in a more realistic manner and also eases the agency review process in a systematic way.”

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Article from Healthcare Management in India by Dr. Arun Bhatt, From guidelines to law

Article from Bio Spectrum on New DCGI expected to takeover in November

Thanks to our readers in India!

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On the Blogroll: Compliance Zen discusses Building Compliance in India

Rebar Interactive has 22 great GCP websites, and more.

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Tufts Center for the Study of Drug Development: Article on Protocol Amendments: One third can be avoided.

Drug shortage at hospitals could be deadly, by Linda A. Johnson, The Associated Press

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You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives and the discussion on risk-based monitoring. I also encourage you to get an email subscription (on the sidebar to your right) or join the GxP Perspectives LinkedIn Group (below).

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Training Opportunities:

Audits & Risk Management

GxP Audit & Risk Management Congress: 20-21 October 2011, Philadelphia, PA. This conference combines both GMP and GCP tracks to maximize the opportunity for cross training, shared best practices, and networking. Two members of the GxP Perspectives LinkedIn group, Janice Wilson and Adi Lampmann, are among the faculty. The conference is sponsored by ExL Pharma and GxP Perspectives is a media partner.

GxP Audit & Risk Management Brochure

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FDA Clinical Investigator Course,
7-9 November 2011, Silver Springs, MD

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There 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.

GxP Perspectives LinkedIn Group

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FDA Clinical Trials: Quality Considerations for Pivotal Studies

When Should Quality Begin?

When should quality preparation begin for a pivotal phase III clinical trial? About once a month I get a call asking for help for a clinical trial because its time to get ready for FDA inspections. I ask “When will the application be filed?” The response? “Soon, very soon.”

It is a good thing to prepare for an FDA inspection. It is even better to prepare at the beginning, reviewing the quality considerations necessary to do the job right by “frontloading quality.” Here are some things I think you should consider. (Please take the survey at the end)

Phase III Considerations for Compliance with the FDA Bioresearch Monitoring Program: by Carl Anderson

The U.S. Food and Drug Administration conducts inspections of clinical trials as part of their Bioresearch Monitoring program. Although all FDA regulated clinical trials are subject to inspection, the large majority of inspections are the result of an application for the approval of an investigational product. Results of an FDA “Bimo” inspection can have a direct impact on the review and approval of an NDA, PMA, or BLA by the agency. FDA conducts inspections of clinical trials for two primary reasons:

1. To ensure the integrity of data submitted to the agency in support of an application.

2. To protect the safety, rights, and welfare of human participants in clinical trials.

The regulations that the FDA enforces for clinical trials are collectively known as the good clinical practice (GCP) regulations. They include 21 CFR Parts 11, 50, 54, 56, 312, 314, 601, 812, and 814. They can be found on the web at: http://www.fda.gov/oc/gcp/regulations.html. In particular FDA Bimo inspections cover the specific responsibilities required of sponsors and investigators covered by 21 CFR 312 Subpart D: Responsibilities of Sponsor and Investigators. For medical devices they are contained in Part 812.

The primary guidance document used for GCPs is the International Conference on Harmonization E6: Good Clinical Practice: Consolidated Guidance. This document is the international standard and the primary GCP regulation in many countries. ICH documents for clinical studies including E6 can be found at the link on the bottom

There are two types of GCP inspections that are of concern for sponsors. The first type is the inspection of clinical investigators at the sites where research is conducted. The majority of FDA inspections are of the investigators. The second type is the inspection of the sponsor or contract research organization. This is a routine inspection for medical device sponsors and is becoming more common at drug sponsors. Although most inspections are at clinical sites, in the event that serious deficiencies are documented, there can be directed inspections of sponsors that can result in serious regulatory action.

QA for the Data Lifecycle

Prior to beginning a pivotal study the sponsor should establish a system of clinical quality assurance. This is a recommendation, not a requirement, of FDA. E6 defines quality assurance (QA) as: “All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with GCP and applicable regulatory requirement(s).” Among the most important QA activities are the following:

Clinical trial materials. They should be produced in compliance with good manufacturing practice (GMP) regulations and qualified by an onsite audit.

Increased Enforcement of
Part 11

Computerized systems including eCRFs. There are many forward looking systems available for electronic case report forms (CRFs) including systems that are internet based. These vendors are not regulated by FDA and do not receive regulatory inspections. The burden is on the sponsor to determine if the vendor provides GCP compliant services. All should be qualified by an onsite audit.FDA has started looking a lot closer at eCRF systems.

Site management organizations (SMOs). These are unregulated organizations that provide support for clinical investigators and recruit study subjects. FDA inspections of sites using an SMO have frequently been cited for noncompliance with GCPs. SMOs should also receive onsite audits.

Central IRBs. These commercial institutional review boards have a better record than SMOs. However, the protection of human participants in research is a central FDA concern. Commercial IRBs should be qualified by an onsite audit.

Randomization services. This might not require an onsite audit and qualification, but the sponsor needs to critically determine that the vendor can supply the required services.

QA Audits of Clinical Sites

Audits of clinical sites. ICH E6 states that: “The sponsor’s audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities…” The sponsor should audit a pivotal clinical trial throughout the data lifecycle. In particular the sponsor should audit problematic sites during the study. It is the sponsor’s responsibility to “secure investigator compliance” if the investigator is violating GCPs. This was the first violation cited on the Sanofi-Aventis Warning Letter and has historically been a major violation cited on FDA Warning Letters to sponsors.

Top enrolling sites should always be audited during the course of the study because of their increased importance for a successful study and the likelihood that the site will receive an inspection by FDA. The sponsor should also audit sites that may be inspected by FDA at the conclusion of the study including data outliers, sites with a history of noncompliance, and sites that do not have a history of FDA inspections.

Database audits The sponsor’s data management activities should have independent QA review. This should include a qualification audit if data management is contracted out. An excellent resource for data management is the Society of Clinical Data Management. They publish a Good Clinical Data Management Practices Guide which is available for purchase on their website below.

Trial master file (TMF) audits: A TMF consists of the Essential Documents section of ICH E6. There should be QA review periodically throughout the study. The failure to adequately document a clinical trial will hinder any application to FDA. The agency field investigators have a saying that, “If it isn’t documented then it didn’t happen.” Take a look at the TMF page at the top of the blog for additional resources.

Conduct Regular GCP Training

GCP training: The sponsor should have a training program that includes initial and continuing training on good clinical practice. The training program should be in writing and training should be documented. At least once a year staff members should attend an outside conference, meeting, or workshop that includes clinical trial professionals that are not the sponsor’s employees.Peer-to-peer interactions are necessary to develop staff

GLP audits: The FDA conducts routine surveillance audits of nonclinical test facilities. An FDA inspector may randomly select a study of the sponsor to track as part of that inspection. Protocols and final reports are collected and sent to FDA headquarters as part of the inspection. The sponsor should always qualify a nonclinical laboratory used for GLP studies submitted to the agency. The new FDA Sponsor Compliance Program (see previous post) gives instructions for looking at nonclinical studies during GCP inspections at the sponsor.

Sponsor audits and mock FDA inspections

Always Prepare for an FDA Inspection

Finally, a sponsor should conduct audits of their clinical management department and conduct “mock FDA inspections” in preparation for the regulatory audits that will inevitably take place after the NDA, PMA, or BLA is filed. Preparing for a regulatory inspection is invaluable for effectively hosting any regulatory agency, in particular FDA. Medical device sponsors need to remember that FDA typically inspects sponsors submitting a PMA. Drug sponsor inspections are on the increase. The “OAI” violation rate for inspections of medical device sponsors was 33% in fiscal year 2007. OAI stands for “official action indicated” the most serious classification.

An OAI classification can cause FDA to delay or reject an application.

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This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)

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Society for Clinical Data Management

ICH Guidance Documents
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FDA Warning Letters to International Companies for CAPAs & Complaints

Warning Letters for CAPAs & Complaint Investigations

In the past 90 days FDA issued five Warning Letters to international firms for GMP failures to adequately investigate complaints. Whether it is GMPs, GCPs, or GLPs FDA is making the case that when things go wrong, it is a company’s responsibility to investigate and implement the necessary corrective and preventative action (CAPA), In the past, FDA was hesitant to issue Warning Letters to firms outside the United States. That clearly is changing as both the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) have issued Warning Letters to companies in Canada, Switzerland, China, Sweden, and India. Although the companies are from diverse locations and range from medical devices, active pharmaceutical ingredients (APIs), and finished pharmaceuticals, one issue connects them all: the failure to adequately address complaints. For the medical device Warning Letters, corrective and preventative actions (CAPAs) figured prominently.

FDA first opened international offices in 2008 in India and China and now has offices in Europe and Latin America as well. The international offices are predominantly focused on GMPs for food, drugs, and medical devices. FDA has also stepped up its inspections of clinical trials in international locations including Russia and Eastern Europe. However, there has not been the corresponding surge in Warning Letters. At least not yet. Here are charges that FDA made in the international Warning Letters:

Failure to Investigate Bacterial Contamination

Claris (India): On April 15, 2010, your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the fungus Cladosporium species. There is no information in the Complaint Investigation Report to show that Claris initiated an investigation to determine the root cause and extent of the problem until April 26, 2010, when Claris received this contaminated large volume parenteral and examined it.

Storz Medical (Switzerland): Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, no protocol, including acceptance criteria, was established for the validation of Change Request (b)(4). Additionally, there was no documentation showing that this change was validated. The change was implemented to fix cracked cooling pumps in the Modulith SLX-F2.

The Warning Letter goes on to say:

Failure to Establish Procedures for Complaints

Failure to establish and maintain adequate procedures to ensure that any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall be reviewed, evaluated, and investigated unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c).

Neoventa Medical AB (Sweden): 1. Failure to establish and maintain adequate procedures for implementing corrective and preventive action that include requirements for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device and that all activities required under this section and their results be documented, as required by 21 CFR 820.100(a)(4) and (b).

2. Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).

Once again the direct connection between the failure to investigate complaints and the failure of a system of CAPA.

Chinese API Manufacturer Hit with FDA Warning Letter

Yunnan Hande (China): Failure to thoroughly investigate complaints for APIs batches that do not meet the United States Pharmacopeia (USP) compendial requirements that may have been associated with the specific failure or discrepancy. In addition, your investigation was not extended to other batches that may also be affected.

Pega Medical (Canada): Failure to establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50(a)… For example, Complaint NCR No. (b)(4) reported…”

Read the Warning Letters:

Storz Medical, AG Warning Letter

Yunnan Hande Biotech Warning Letter

Claris India Warning Letter

Pega Medical Warning Letter

Neoventa Medical AB

FDA International Resident Posts

And What About Clinical Trials?

At a recent FDANews conference FDA representative Ann Meeker-O’Connell, M.S., Division of Scientific Investigations, Office of Compliance CDER/FDA, said,

Clinical Trial CAPAs Face Different Challenges

“But, clinical trials are inherently variable systems with a goal of producing reliable data for regulatory decision-making . . . How can this be reconciled with a quality system framework originating in mass manufacturing?”

That is a very good question and one that many of us have been wrestling with. However, it is clear that FDA has been taking on the question of the international nature of the drug and device industry, including manufacturing and clinical trials.

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Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

UPDATE: There is a very interesting Important Notice to IRBs that is on the FDA website. Sort of a Coast IRB redux.

Public Comment Period is Open for New FDA Draft Guidance:
FDA Draft Guidance on Electronic Source Data in Clinical Investigations

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Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

On FDA’s Website there are Two New Warning Letters from FDA to Clinical Investigators that show the need to effectively respond to a Form FDA 483, Inspectional Observations, with a well thought out CAPA Plan.

Response Letters to a Form FDA 483, Inspectional Observations

How Should You Respond to a Form FDA 483?

What is an adequate response to a Form FDA 483, Inspectional Observations? That question was discussed by two representatives of FDA at a training workshop hosted by the Pacific Regional Chapter of the Society for Quality Assurance and the Organization of Regulatory and Clinical Associates – Northwest. The workshop, held on 4-5 November 2010 in Seattle, featured discussions by Chrissy J. Cochran, PhD, from the Division of Bioresearch Monitoring (BIMO) at the Center for Devices and Radiological Health (CDRH) and Mihaly S. Ligmond, Consumer Safety Officer, Division of Domestic Field Investigations, Office of Regulatory Affairs (ORA). ORA is the field organization that conducts most FDA inspections. Both Cochran, who spoke by teleconference on the 4th, and Ligmond, who attended on the 5th, stressed the do’s and don’ts of responding to an FDA 483.

The Form FDA 483

Both FDA speakers stressed that the 483 is the preliminary observations of the field investigator, not the final compliance determination of the Agency. Both emphasized that there was no requirement to respond in writing to a 483. However, both told the training session that if there are issues identified on a 483, then a clear written response can help prevent enforcement action, including a Warning Letter, by FDA. Cochran discussed a few ineffective FDA 483 response letters received by CDRH. They included a clinical investigator who was using an informed consent form without all of the required elements required by 21 CFR 50.25. These elements include a clear statement of research; alternative procedures; a discussion of confidentiality and other important information. The clinical investigator complained that: “You cited us on a technicality.” This was a clear and significant violation of FDA clinical trial regulations and this was not an acceptable response.

Cochran gave an example of an adequate response to an FDA 483 for protocol violations. The response included a copy of a written procedure developed to prevent recurrence of the violation. The procedure was presented to a seminar for study staff with a sign-in sheet with the date of the seminar. It included implementation dates with a review scheduled after three months to determine the effectiveness of the corrective action.

The response to an FDA 483 should go to both the District Office and to CDRH, Cochran said. She stated that it is the assessment at BIMO that makes the final compliance determination for Bioresearch Monitoring inspections. She reviewed the issues that BIMO considers when reviewing an establishment inspection report (EIR) and a Form FDA 483, Inspectional Observations. These include:

• Are the FDA 483 observations actual violations of the regulations?
• Are there additional violations in the exhibits submitted with the EIR?
• Are the observations documented with exhibits or discussion in the EIR?
• Are the observations significant?
• Did the inspected party address the issue in their response?
• Is the response adequate? “We will carefully look at it.”

Ligmond, who is a National Expert for drug good manufacturing practice (GMP) inspections, gave the following recommendations for a response letter to an FDA 483:

• Set a reasonable timeline for taking action;
• Initiate a “Global Response” if the deficiency can impact other areas;
• Include details and attachments;
• Be comprehensive;
• Address disagreements with the observations;
• As a courtesy, copy the investigator

The FDA 483 is the Preliminary Observation of the FDA Field Investigator

Both Cochran and Ligmond restated the new FDA policy for written responses to an FDA 483 if the response is to be considered by FDA prior to issuing a Warning Letter. That response time is 15 business days from the date the FDA 483 is issued. Ligmond gave an excellent recommendation to avoid possible disputes on FDA 483 observations. “Address misunderstandings promptly, courteously, and with the facts,” he said. He discussed the importance of a daily wrap-up session o clear up any disagreements or inaccurate information that may have been given to the FDA field investigator.

CAPA

Corrective and Preventative Action, or CAPA, was discussed by both speakers. Ligmond said that a CAPA plan should address problems completely and in a timely manner. Cochran said that a good CAPA plan should assess the root cause of deficiencies; identify the problems; evaluate the extent of problems; give a clear timeline, describe the CAPA being taken; and reassess the root cause.

Inspection preparedness was also discussed. Ligmond said to spend each day as if you were going to be inspected by FDA. They stressed the importance of Mock FDA Audits in preparing staff for inspections.

ALWAYS Respond to a Form FDA 483

My own experience is that it is always a good idea to respond to an FDA 483. If there is a problem, then give clear details on how the problem is going to be fixed, with specifics such as a timeframe. If you disagree with the observation, then follow Ligmond’s advice to address it “with the facts” and with documentation of the facts. FDA rarely will accept excuses such as “I thought my study coordinator was going to do that.” However, if there is a legitimate response, you should make it in a clear, respectful manner. The 483 responses I have worked on always included specific actions, specific dates, and a specific person or department accepting responsibility for ensuring that the corrective action takes place. And they always include documentation of corrective actions. If it isn’t documented, then it’s just a rumor.

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A new feature from FDAzilla on FDA 483s–

Read the Press Release on 483s

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HIV/AIDS Drugs: Funding in Question

HIV/AIDS Crisis Continues

The economic downturn has hurt funding for HIV/AIDS drug subsidies for life-sustaining programs that provide antiretroviral drugs to patients who cannot afford them. In a July 1st article by Kevin Sack in the New York Times, there are eleven states that have closed enrollment to the program including Florida, with the third highest number of people with HIV/AIDS after California and New York. The lack of drugs can cause people who are HIV positive to develop full blown AIDS, increase transmitting the virus, and require expensive hospitalizations. Other measures include paring back the number of drugs on the approved formulary and placing patients on waiting lists to receive necessary treatment.

It is a stark reminder that AIDS is still a major public health issue, not only in developing countries in sub-Saharan Africa, but in communities across the United States. To get a better perspective in my own home town of Tacoma, WA, I asked Duane Wilkerson, Executive Director of the Pierce County AIDS Foundation how bad the problem was here. Duane gave me the reality on the ground in 2010.

GxP Perspectives: Does the cutback in funds mentioned in the NY Times article impact local agencies such as the Pierce County AIDS Foundation (PCAF)?

Duane Wilkerson (DW): Washington State is a little luckier than some states. People who are diagnosed with AIDS are able to get AIDS drugs in a variety of ways. Through the state ADAP program and different insurance options for drug coverage, no one in Washington State goes without AIDS drugs who need them.

GxP Perspectives: How have the current economic problems impacted non-profit agencies like PCAF?

DW: We are seen cutbacks in prevention more than client services. Because of the State budget crisis combined with a reduction from CDC for prevention services, several of our prevention contracts have been reduced from the original award levels.

GxP Perspectives: Have you seen an increase of clients who had previously stabilized their healthcare regimen?

DW: Yes. We saw an increase of 25% in 2009 from 2008. Much of this increase represented clients who had not needed our services for awhile, but came back because of the effect of the economy on their economic situation and consequently their health status.

GxP Perspectives:What is the most cost-effective way to use funds for the treatment/prevention of HIV/AIDS?

An Ounce of Prevention...

DW: This has answers at several layers. First prevention is clearly the most cost-effective strategy. If you compare the cost of an effective, evidenced-based prevention program per person to the cost of a lifetime of medical/health/drug care for someone who is living with AIDS, you will see a huge difference. Within effective, evidenced-based prevention programs, group-level interventions are consistently evaluated as being the most effective and cost effective. One-on-one level programs are very cost/labor intensive, though some are very effective; community-level programs are often not as expensive, but affords very little program effectiveness in critical areas of behavior change (e.g., reducing sexual partners, using condoms more consistently, etc.). Treatment programs, started early in the progression of the disease can be cost effective (compared to later initiation of treatment), in they can keep the viral load at a much lower level for much of a person’s life; allowing them to live longer and with better health.

GxP Perspectives: Are clinical trials the answer to the AIDS pandemic? Is there a magic bullet in the works?

DW: Clearly not yet. Will they ever be? It seems a moot question for me at the moment. There have been so many “promising” research trials, in the last ten or more years, that have cost enormous amounts of money. To date, none of them have been successful. Certainly we can’t wait or count on a magic pill. We must increase the prevention efforts because they have been shown to work.

GxP Perspectives: Readers of the Blog are from across the country and are also in international locations. I know that local organizations need funds but how can people help out on a national or international level?

DW:

Needle Exchange Programs Have Proven Effective In Preventing the Spread of HIV

I think one of the most important ways to contribute to (ending) the epidemic, on the national and international level ,is getting involved in policy decisions that guide how prevention is done. For example, in the U.S., one of the most successful behavioral interventions that we know of is needle/syringe exchange. There is no serious debate in the field that this works, and works well. Yet because of political decisions the U.S. government will not fund exchange programs with any federal funds. In addition they put these restrictions on funds for international efforts (through PEPFAR), along with other political motivated restrictions such as not funding any program that also provides family planning services. These restrictions have nothing to do with good public health practices and everything to do with politics.

GxP Perspectives: What else should we be doing about the AIDS pandemic?

HIV Infections Continue in the United Stas and Worldwide

DW: In the U.S. we can keep the issue of HIV infection in the forefront of public health concerns. In a country which has no attention span to speak of, too many people assume it is no longer a problem. This despite the fact that 56,000 new infections are still occurring in this country each year. Another important contribution would be to be open and public in the support of people who are HIV infected. Stigma and discrimination are still very much alive and contribute to the pandemic through ignorance, fear, and oppression of those who are infected. Finally you can be tested if you have engaged in any of the risk behaviors that can transmit HIV (e.g., unprotected sex with a partner whose HIV status is unknown, using unsterile needles for any kind of reason, but particularly injection drug use).

GxP Perspectives: Why is it important to society that people who are HIV positive receive these expensive drugs?

DW: Because it has a direct impact on public health and the economy. People who are on anti-viral medications (HAART therapy) have a lower viral load (the amount of the HIV virus in their blood system). This in turn makes them less able to infect others compared to those with high levels in their blood. Fewer infections will occur with more HIV infected people on good medications. This then has obvious economic implications related to the cost of treated each person who is HIV positive.

AIDS.GOV for additional informating on HIV/AIDS

Pierce County Aids Foundation

And on another issue requiring our attention:

Update: NIH has provided funding for ten international malaria research centers. Read the 8 July 2010 Press Release

GxP Perspectives LinkedIn Group

Drug Products: How Many Names?

So Many Drugs- So Many Names

Have you ever wondered why drugs can have so many names and who keeps track of it all? It turns out that there are a number of different organizations that have some responsibility in the naming of drug products and it can be pretty confusing. Fortunately we have a Guest Commentary by Louise Johnson to help make sense of it all. Louis sent this out to her email informational list a few weeks ago and I pleaded with her to use it on the Blog. This is her second Guest Commentary after her popular “Ten Tips for Filing Regulatory Submissions.” I know I could have used Louise when I was auditing some cardiology studies that had a host of prohibited concomitant medications, all described differently. So here is a post you can bookmark for future reference. Louise’s list of how many names of drug products is pretty extensive.

Guest Commentary:

There are several types of names commonly used for drugs and biologics. Some names, such as the trade name, are selected by the sponsor, while others are assigned by nomenclature bodies. What are the different types of names and who selects them?

The chemical name is assigned following rules defined by the International Union of Pure and Applied Chemistry (IUPAC). The US national committee under IUPAC is the National Academy of Sciences. While there may be more than one chemical name in use, the IUPAC name is considered the official chemical name. The chemical name is included in the Description section package insert for small molecules.

The generic name (also referred to as the nonproprietary name or the common name) is selected by the United States Adopted Names (USAN) Council. USAN is sponsored by the American Medical Association, the US Pharmacopeial Convention, and the American Pharmacists Association and works with the international organization, the International Nonproprietary Name (INN) Programme of the World Health Organization (WHO). Sponsors can suggest a generic name and apply to USAN for adoption. USAN can reject the proposed name and suggest alternatives. Once the sponsor has accepted the proposed USAN name, USAN requests an INN from the WHO. The INN Programme can also reject the name and suggest alternatives. Upon final agreement, USAN adopts the name, informs the sponsor, and publishes the name on their website. FDA accepts the USAN name as part of NDA or BLA approval. Approval may be delayed if a simple and useful nonproprietary name does not exist and if one is not proposed in the application. The generic name must be included in all product labeling as part of the product name.

The established name is the name accepted by FDA for official use and is the name listed in the USP. The established name is usually the same as the USAN generic name, but FDA does have the authority to reject the name if it is not simple and useful. Note that an established name is also defined for the drug product following USP conventions. The established name is used in all official monographs and legal documents.

FDA Approves Proprietary Drug Names

The trade name (also referred to as the proprietary name) is proposed by the sponsor and approved by FDA. The trade name is owned by the sponsor, is protected as intellectual property, and is trademarked. Trade names may not imply benefit and must be distinct from trade names of products already on the market in order to avoid product mixups. FDA has recently provided Guidance for Industry on trade name review. When the trade name is used in product labeling, it must be accompanied by the generic name. While the other names can be used by multiple companies for different products, the trade name is used only by the innovator company.

The trivial name is an acronym or shorthand version of the generic name that is often used in research papers, protocols, or reports. The trivial name has no legal status and is not an approved name.

~~~~~~~~~~~~~~~~~~~~~~~~~~~
By Louise Johnson, M.S.
Senior Consultant, Regulatory Affairs
Biologics Consulting Group

Read Louise’s previous Guest Commentary Ten Tips for Filing Regulatory Submissions

Save The Date: On 4-5 November 2010 the Pacific Regional Chapter of the Society for Quality Assurance (PRCSQA) and the Organization of Regulatory and Clinical Associates (ORCA), a Pacific Northwest based organization, will co-sponsor a Fall Training on regulatory compliance topics in Seattle, WA.

The PRCSQA LinkedIn Group will update the agenda for the training. PRCSQA Fall Training workshops have traditionally been “at cost” and are an affordable training opportunity. The sessions will cover both GCPs and GLPs with speakers lined up on vendor management, quality systems, and GLP updates.

And still another Update: Now you too can contribute to FDA history by suggesting an acronym to the Agency. I kid you not. FDA has a link where you can suggest a new acronym or abbreviation for the Agency’s use.

FDA Acronyms

Bioresearch Monitoring Information System: This FDA system with information on FDA BIMO inspections is updated quarterly. The latest update has been released with info on Q2 inspections.

GxP Perspectives LinkedIn Group

CAPA Basics- Corrective And Preventative Action

CAPA Basics

When developing a quality management program you need to discuss the basics of CAPA: corrective and preventative action, and how to come up with a CAPA plan that resolves the root causes of violations. In a guest commentary, veteran GxP consultant Barb Immel discusses CAPA basics. I first met Barb when she was teaching a 3-day drug development course at UC Extension and had invited me as a guest speaker. I sat through the entire three days and learned a lot.

Guest Commentary:

CAPA Basics By Barbara K. Immel

Poor corrective and preventive action (CAPA) and investigations continue to be among top FDA Form 483 deficiencies issued to drug, biologic, and medical device manufacturers. And FDA has been issuing warning letters citing inadequate corrective action to clinical investigators, institutional review boards, contract research organizations, and sponsors. It’s in everyone’s self interest to improve the quality of investigations and CAPA. The most important point to remember?

The depth and intensity of an investigation should match the potential risk to the patient.

1. Start with the requirements. Always follow all applicable regulations and standards, and go above and beyond the minimum requirements. Although the only organizations that are required to establish a CAPA system are medical device manufacturers, it has always been either a requirement or an expectation that all organizations in our industry will perform thorough investigations and implement effective CAPA. Helpful passages include, but are not limited, to:

Device CGMPs. Establishing a CAPA system is a CGMP requirement for medical device manufacturers producing product for the US (21 CFR 820.100).

Drug CGMPs. Conducting certain investigations and documenting and justifying deviations is required for manufacturers making product for the US. Inadequate investigations are a frequent CGMP deficiency (21 CFR 211.192).

Good Laboratory Practice

Preclinical Requirements. Taking corrective action is required in the GLPs (21 CFR 58) for testing facility management (21 CFR 58.31), the study director (21 CFR 58.33), Clinical Requirements. And taking effective corrective action is implied in the GCPs. Relevant sections include but aren’t limited to the Responsibilities of Sponsors (21 CFR 812.40) and Responsibilities of Sponsors and Investigators (21 CFR 312 Subpart D).

2. Establish good surveillance. Carefully think about the data you need, and the speed with which you will require being notified. A surveillance system is only as good as the information it receives.

• Conduct thorough, frequent audits (most internal operations should be audited at least once a year, and critical suppliers should be audited frequently, such as once every 12-18 months). Ensure audits are done by experienced personnel, and that any identified issues are promptly addressed.

• Require that all employees immediately report to their supervisor when they deviate, make a mistake, or notice something unusual. Require that sites notify you rapidly of any issues or potential issues.

• Set up an effective trending system, to identify potential issues before they become a fire.

• Regardless of where you work in the industry, check out the following documents for ideas:

o AdvaMed Points to Consider When Preparing for an FDA Inspection under the QSIT Corrective and Preventive Action Subsystem:

o Global Harmonization Task Force Proposed Document: Quality Management System — Medical Devices — Guidance on corrective action and preventive action and related QMS processes:

www.ghtf.org/sg3/sg3-proposed.html

Laboratory Requirements:

If you work with a laboratory, see FDA’s Guidance for Industry: Investigating Out-of-Specification Test Results for Pharmaceutical Production

• Ensure your system will allow you to notify FDA of any problems concerning your product or clinical trial within FDA required reporting timeframes (i.e., a field alert, medical device report, biologic product deviation report, adverse event or serious adverse event, etc.).

• Always include a link between your investigation and CAPA procedures and your FDA reporting procedures, including your recall procedure.

Review Recall Procedures

Any potential recall situation should immediately be brought to the attention of your QA executive. For recall SOP ideas, see FDA’s regulation (21 CFR 7) and FDA’s Guidance for Industry: Product Recalls, Including Removals and Corrections. Test your recall system at least once a year.

Remember: Each FDA District Office has a Recall Coordinator.

http://www.fda.gov/Safety/Recalls/IndustryGuidance/ucm129259.htm

3. Create (or improve) your SOP(s) and systems. Every organization should have a failure investigation procedure that states the threshold for initiating an investigation. The decision whether to investigate should always be made by an experienced QA employee, and documented.

• Periodically ask employees or others using your system what’s driving them crazy about it, and act on the results.

• Make sure your system requires the early categorization or determination of risk, and the ability to rapidly escalate the importance of items. Your system should include how management will be routinely informed of ongoing investigations and CAPA activities, and how they will be immediately informed of critical issues.

4. Define your terms. For medical device companies, ISO 13485, Medical devices – Quality management systems – Requirements for regulatory purposes, and ISO 9001, Quality management systems –

Define Your Terms!

Requirements, define corrective and preventive action. Since complying with these standards is required to sell devices in Europe, Canada, and Australia, it makes good business sense for device firms to use these definitions. Drug and biologic companies, and clinical groups, are under no such requirement, but define your terms and provide training to all employees so everyone is using the same terminology.

The ISO definitions are:

• Corrective Action: Action to eliminate the cause of a detected nonconformity or other undesirable situation.

• Preventive Action: Action to eliminate the cause of a potential nonconformity or other undesirable potential situation.

5. Train employees. Provide frequent, ongoing training to all employees or staff. Don’t forget to train sales representatives on what a customer complaint is, and how they should rapidly report any that they receive.

• Provide training on the following to individuals performing investigations:

o Your investigation and CAPA procedure(s)
o All applicable regulations and standards
o Root cause analysis
o Solution criteria*
o How to perform an investigation
o Your documentation and reporting requirements
o Report writing (since employees may be moving from simply filling out a form to creating a written investigation report)
o Interviewing (since investigators will need to be able to interview individuals at all levels)

*All solutions should prevent the recurrence of the problem, should not cause an unacceptable problem, should be within the control of your organization to enact, and should provide good value for their cost.

• Teach everyone the key stages of an investigation:

1) identification and definition of the problem,
2) determination of whether to do an investigation (categorization/risk analysis),
3) planning the investigation,
4) root cause analysis,
5) identifying appropriate corrective and preventive action,
6) implementing the action, and 7) measuring the effectiveness of the action.

• Train everyone to carefully evaluate and select possible CAPA actions before they are implemented, and to confirm the effectiveness of the CAPA – and that it didn’t cause a greater problem – after implementation (the effectiveness checks).

• And teach everyone how to do a basic or preliminary investigation. Only ask experienced investigators or employees to perform more serious or difficult investigations (follow-up investigations).

By Barbara K. Immel

For further information take a look at Barb’s website:

http://immelresources.com/

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In News from GxP Perspectives:

CAPA Plans for Clinical Trials

Protocol Violations: Root Cause Analysis

Updates posted 28 JAN 2011- Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

Public Comment Period is Open for New FDA Draft Guidance:
FDA Draft Guidance on Electronic Source Data in Clinical Investigations

GxP Perspectives LinkedIn Group

Paying for healthcare? “Tax the rich,” AP poll says

Maybe Al Franken is right. The comedian turned liberal lawmaker raised some eyebrows when he joined conservative Republicans in opposing taxes on medical device manufacturers to pay for healthcare reform. It turns out that an AP poll finds that most Americans also have a different idea on how to raise funds. They agree with Franken on device taxes. Instead, they want to tax the rich (what a novel idea). Here’s what AP says:

“Lawmakers also are looking at levying new taxes on insurance companies, drug companies and medical device makers. But the only approach that got majority support in the AP poll was a tax on upper-income Americans. The House bill would impose a 5.4 percent income tax surcharge on individuals making more than $500,000 a year and households making more than $1 million.”

FDA Warning Letters Hit Candy Cigarettes & Clinical Investigator

FDA’s new Tobacco center put out 14 Warning Letters to internet purveyors of candy cigarettes. FDA seems very serious about not letting flavored cigarettes onto the market. Now about menthol….

The Center for Drugs also issued a doozy of a Warning Letter to a clinical trial site in Southern California. Among the shortfalls are: failure to supervise the investigation and numerous protocol violations. Also, the investigator failed to have the IRB approve changes in research activity. New protocol amendments showed additional hazards and risks associated with the study drug but the investigator said nary a word to the IRB. That’s a Warning Letter in and of itself. Finally, the investigator was creamed on failure to report Serious Adverse Events as instructed by the protocol. It appears to me that some of these SAEs are disease progression. It may be a case of the sponsor writing violations unnecessarily into the protocol. However, in this case we have a textbook case of the investigator not doing the job.