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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Please join your industry colleagues in completing the 2012 TMF Reference Model Survey, and use results to inform your TMF best practices.

https://www.surveymonkey.com/s/FPP8DCF

This fifteen minute survey is designed by members of the TMF Reference Model team to provide valuable insight into Trial Master File practices, both paper and electronic, to identify common problem areas, assess changes in practice and reveal opportunities for improvement. All respondents who complete the survey and provide contact information will be provided with the survey results.

Data collection closes June 1st; please join us today.

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What is Your viewpoint on IP labeling? Please comment and let us know.


India: Quality for Clinical Trials

March 1, 2012

India clinical trials quality assurance

Quality Systems in India

Are Quality Systems in place in India, where the clinical trials industry is exploding?Do clinical trials professionals have the knowledge, skills and experience to run clinical trials where the rights, safety, & welfare of human subjects is protected and where data are reliable for submission to FDA and EMA> In this Guest Commentary QA professional Anusha Reddy demystifies the GCP process in India outlining her approach to quality in clinical trials.

This marks the first edition of GxP Perspectives as a monthly blog. It has been too much work for one person to keep up with a weekly schedule. I will be using the GxP Perspectives Linkedin Group to keep on top of current developments with FDA, as well as discussions by group members. Also, youcan subscribe to the blog on the button to your right on the sidebar.

Join the GxP Perspectives Linkedin Group Here

Improvising Quality in Clinical Trials

By Anusha Reddy

Over the last decade Clinical Trials in India have increased very rapidly in number. India has made a name for itself in the international pharmaceutical field as an ideal destination for worldwide companies to conduct clinical trials which is a test for both the government and the private sector to create a balance between ethics and trade The rise in the business brought sharp focus on the need to manage quality while conducting clinical trials.A need was, however, felt to develop our own Indian Guidelines to ensure uniform quality of clinical research throughout the country and to generate data for registration for new drugs before use in the Indian population. An Expert Committee set up by Central Drugs Standard Control Organisation (CDSCO) in consultation with clinical expert has formulated GCP guideline for generation of clinical data on drugs.

The Drug Controller General of India (DCGI) has introduced several guidelines and regulations, in an effort to maintain and ensure credibility, integrity, safety, well being and quality of clinical trials, some which includes guidelines on approval of clinical trials, CTD, Clinical trial Inspection, registration of clinical trials, CROs, and Ethics Committee’s. It constituted NDAC to review applications of new drugs and clinical trials, introduced prescreening of applications in order to expedite and streamline the process of application by ensuring completeness and has recently made compensation mandatory for injury or deaths during trials and which would increase the number of volunteers and patients going for a trial in India, according to experts.
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quality clinical trials in India

"Each Stage of Data Handling"

Quality in clinical trials should be applied to “each stage of data handling” to ensure that all data are reliable and have been processed correctly. Clinical trials are carried out to allow safety and efficacy data to be collected to provide information for industry and regulators to make decisions about the safety and efficacy of the interventions. Activities like monitoring and auditing are performed in order to ensure that the quality exists and the study is conducted in accordance with the SOPs, Protocol, GCP and applicable regulatory requirements. Pharma and Biotech firms are looking for several different strategies in clinical trials to ensure the highest quality of data. This article tries to discuss on describing and executing the quality in clinical trials.

A good quality clinical trial should, address an important question, have the potential to make an actual difference to patients, use the finest available research techniques, generate significant data, be scientifically and ethically sound. Recognition of GCP at the sponsor, CRO and the investigator site will improve the quality of clinical trials and finally leads to the acceptance of clinical trials.

clinical trials quality India

"Ability to Satisfy Stated or Implied Needs."

As per ISO (International Organization for Standardization) quality is defined as the features and characteristics of a product or service that bear on its ability to satisfy stated or implied needs. In clinical trials, poor quality has much more serious outcomes than discontented customers. Failure to ensure quality in clinical trials can result in undue harm to research participants, invalid data, and consequently, wrong conclusions about the safety and efficacy of the drug being tested. Additionally poor quality is a call for a regulatory inspection.

Determined efforts to improve quality in clinical trials have increased noticeably over the past decade. Recently the Department of Medical Education has imposed a temporary ban on clinical drug trials and research projects in all government and private medical colleges and hospitals in the Karnataka State, India; however, later it was assured that no such measures are being undertaken. The reason behind such decision was especially lack of guidelines to regulate drug trials. An expert committee was set up to study and frame guidelines to regulate and re-organise clinical drug trials, which is a step towards a quality clinical trials.

quality India clinical trials

The Consequences of Poor Quality

There are several reasons for poor quality in clinical trials and preventing them all is not an easy task. The objective should be to limit their number and their effect on the trial outcomes. This can be achieved by taking steps at the initial stage in protocol development and at the trial set up phase to obtain a high quality data in clinical trials; however, this alone does not result in high quality. Furthermore, planning should be accompanied by adequate oversight through proper routine monitoring and auditing of the trials with necessary corrective and preventive actions (CAPA) in place.

Measures should be taken to promote quality improvement in clinical trials by following standard operating procedures and implementing good documentation practices while performing study activities like drug accountability, Informed consent process, Safety reports, protocol deviations/violations and other protocol related activities which will provide reliable results and error free data when submitted to regulatory agencies for approvals.

A quality system proposition to good clinical practice conformance will establish quality in clinical trials by identification and setup of standards, applying them by those involved in the conduct of clinical trial, tracking the areas that are non-complaint with the standard procedures or applicable regulatory requirements, take actions to prevent the recurrence in future in the identified areas.

quality in India

Developing Metrics

Developing and using metrics that are meaningful within an organization facilitate in measuring the quality in clinical trials. For example, preparing a protocol from the stage of drafting to finalizing, here with increase in amendments the time increases and quality is reduced (but number of amendments is often not the reflection of protocol quality). Other example for measuring the quality includes the number of data clarifications forms (DCFs) raised per case report form (CRF); increase in the number of data queries indicates the poor data quality. Based on these metrics one can measure the quality and can improve those areas.

In Conclusion, systems with procedures or measures that assure the quality of every aspect of the clinical trial should be implemented. Quality should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. This extent of transparency and accountability of clinical trial processes ensures ongoing quality control and quality assurance, but in addition, makes it easy to assertively address inquiries from regulatory agencies.

Useful Links:

Indian GCP

Clinical Trial Registration

Prescreening Checklist

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Training Opportunity:

The 3rd Proactive GCP Compliance Conference taking place April 2-4 in Arlington, VA – GCP Conference Website. Leading GCP experts from Lilly, Pfizer, J&J, Novartis, Shire and many more address risk-based approaches to clinical quality that meet requirements and ensure patient safety. Special 15% discount off of the standard registration rate for GxP Perspectives readers. Register online at: GCP Conference and use discount code: P439GXP

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DIA Regulatory Conference this April in India

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In News From FDA:

FDA has issued the final guidance, “IRB Continuing Review after Clinical Investigation Approval.” GCP Guidance Documents may be found here: FDA GCP Website. The new guidance is on the right in the section “In The News.”

From: A Message from the Commissioner
Sent: Wednesday, February 29, 2012 04:14 PM
To: FDA-Wide
Subject: Announcement re Chief Counsel

Dear Colleagues,

I am thrilled to announce the permanent appointment of Elizabeth Dickinson as the Chief Counsel of the Food and Drug Administration, effective Monday, March 12, 2012.

As many of you know, Liz has had a long and distinguished history at the Agency; she joined the Office of the Chief Counsel in 1994. Over the years, Liz has served as legal counsel to the Center for Drug Evaluation and Research and the Office of the Commissioner on innovator and generic drug review issues, orphan drug development, and biosimilars; has implemented pediatric exclusivity and pediatric drug development programs; has worked closely with the Department of Justice on dozens of cases addressing Waxman-Hatch issues and preemption; and has coordinated the development of the Office of the Chief Counsel’s flexible workplace program.

A graduate of the University of Massachusetts and Northeastern University School of Law, Liz is highly regarded by both her internal colleagues and those across the food and drug bar. Over the years, Liz has received numerous awards for distinguished service, leadership and her outstanding legal skills.

Liz has been serving as Acting Chief Counsel since August 2011, and we have been grateful for her hard work and dedication each day that she has been on the job. It is terrific to know that she will be serving the Agency in this role permanently as we move forward. Please join me in congratulating Liz.

Sincerely,
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs

We have some excellent comments on this post. Please join the discussion and add your own thoughts


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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Please leave a comment on this question. Thanks!
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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.

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

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Informed Consent & Research Ethics Discussed at WIRB Annual Training Seminar

October 2, 2011

Seminar on Informed Consent and Research Ethics

WIRB Training Seminar was Held in Seattle, WA

“Obtaining consent does not make an unethical study ethical,” Dr. Marjorie Speers told the Annual Training Seminar of the Western Institutional Review Board (WIRB). Speers is the President and CEO of AAHRPP (Association for the Accreditation of Human Research Protection Program). She pointed out that, although many IRBs focus on the informed consent process, protocol design is an equally important ethical consideration. The focus of this year’s seminar was informed consent and the speakers’ presentations led to some lively discussion on consent forms, protocol design, research in the developing world, and financial disclosure.

The seminar, which WIRB opens to research professionals in the Puget Sound, features national experts on bioethics and the regulation of IRBs. Among the speakers were Dr. Speers; Dr. Jerry Menikoff, Director of the Office of Human Research Protections (OHRP); Dr. Vincent Ahonkhai, Senior Regulatory Office, Bill and Melinda Gates Foundation; and, Dr. Jeremy Sugarman, Professor of Bioethics and Medicine, Johns Hopkins University. The University of Washington and the Fred Hutchinson Cancer Research Center co-sponsored the seminar with WIRB.

informed consent and research ethics

Simplifying the Informed Consent Process

A recurring theme was the need to shorten consent forms to make them more accessible to research subjects. Dr. Speers referred to most of the required elements of informed consent a “required disclosures,” stating that “disclosures” was a preferrable term. During discussion periods there were several comments that the disclosures had more to do with legal concerns than with involving the research subject in an informed consent process. Dr. Speers stressed that, “too much information is no information.”

Dr. Speers spoke of the need to involve communities as well as the individual research participants. “Communities can be harmed and benefitted by the research,” maintained Speers. “Generally, the public does not understand the drug development process,” Speers said, the aim of gaining new knowledge.

The seminar discussed some humorous examples of researchers not understanding sensibilities in the developing world. For example, informed consent forms frequently use units of measure such as a teaspoon or quarter cup of blood taken for laboratory analysis. However, when the research was in sub-Saharan Africa, because researchers were using units of measurement most common in cooking, potential subjects assumed that the blood was going to be cooked, not analyzed. This led to worries about witchcraft, which was clearly not the intent of the researchers.

WIRB invited a research participant, Debbbie, to address the seminar. Debbie had participated in many cystic fibrosis studies in the past 20 years. She talked about how access to healthcare and money were her primary motivations for participating in a clinical trial. She had lost her health insurance a few months before enrolling in the study. Then she developed pneumonia. During the run-in phase of the study there was a “cleanout” using antibiotics, a common practice in CF studies. Participating in the clinical trial directly benefitted her healthcare. One of the reasons she enjoyed research participation was the access to healthcare and cutting edge developments in the treatment of cystic fibrosis.

The Influence of Money on Research Ethics

Money was a major topic of conversation, as always at a meeting discussing bioethics. Debbie was asked, “how much of a factor is it?” Quite a lot, she replied. Speakers discussed the question from the perspective of financial disclosure. Dr. Speers said that any financial interest by a member of the research team should be an expected disclosure. Others pointed out that the only type of financial relationship that significantly affected potential research participants was when the researchers had an equity interest in the research drug. But not always in ways you might expect. One potential subject said that when learning the PI owned stock in the company sponsoring the research, they thought, “the drug must work,” and wanted to participate.

There was one embarrassing moment for quality assurance professionals during a talk by Dr. Maria Greenwald, a researcher from California. She had recently been audited by a sponsor QA auditor who cited her for failing to report “protocol violations” to the IRB. The protocol required periodic laboratory tests for calcium levels, which were a concern for the investigational product.

Research Ethics and Audit Findings on Calcium Levels

Elevated Calcium Levels

When blood tests revealed significantly increased calcium levels for one research subject, Dr. Greenwald ordered laboratory tests at every study visit, more frequently than the protocol required. She considered this necessary for patient safety using her medical judgment, as required by the Form FDA 1572. The auditor disagreed and insisted that she had violated the protocol.

I remember my own inspection training in the FDA Bioresearch Monitoring program. “Never argue the practice of medicine with an MD,” I was told. When Dr. Greenwald said that she ordered the lab tests for patient safety according to her medical judgment, the auditor should have accepted it and merely noted it in her report.

The public seminar concluded with David Forster, the Chief Compliance Officer for WIRB pointing out a three-page informed consent form approved by WIRB during the first year of its existence. It had all of the required elements, or disclosures, and was simple and to the point. He challenged WIRB board members to see if it was possible to return to a clear, simple consent form. Most appeared up to the challenge.

Carl Anderson
GxP Perspectives
02 October 2011

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Good Documentation Practice: Thanks to Jerry Chapman at IPQ Publications for this useful resource list for GDP Guidance Canon

Information about IPQ Publications

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Next Week: Veteran GCP educator, David Montgomery opines on the
FDA Draft Guidance on Risk-Based Monitoring

Six Weeks Left to Comment on Risk-Based Monitoring!

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

The Federal Register Docket Number is FDA-2011-D-0597

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Just released– FDA Draft Guidance for Medical Devices: De Novo Classification Process (Evaluation of Automatic Class III Designation)
Read the Federal Register Announcement

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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).

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.

GxP Perspectives LinkedIn Group

Follow GxP Perspectives on twitter: @GxPPerspectives

Follow GxPPerspectives on Twitter

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Pacific Regional Chapter SQA Fall Training 10-11 November at Allergan in Irvine, CA. The training will feature a debate which should be an interesting development in training workshops: Debi Garvin, MS, RQAP-GLP and Paula Parsons: Debate: The role of CAPA in a GLP environment.

PRCSQA Fall Training


Clinical Trials in India: An Overview

September 25, 2011

India flag map

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

India medical facilities for Clinical Trials

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.

India flag

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.

clinical trial

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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Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011

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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:

training GxP

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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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.

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

Follow GxPPerspectives on Twitter


FDA Guidance on Risk-Based Monitoring, Part II

September 17, 2011

FDA risk based monitoring

New FDA Draft Guidance Document

FDA’s new draft Guidance for Industry: Oversight of Clinical Investigations — A
Risk-Based Approach to Monitoring (August 2011) is the subject of a great deal of discussion among clinical trial professionals. On the GCP LinkedIn group some have written about their concerns that “centralized monitoring” would severely limit a sponsor’s involvement with clinical sites. Others have pointed out that the emphasis on developing a monitoring plan should ensure that appropriate resources are tageted to where they are needed.

Two weeks ago GxP Perspectives published a Guest Commentary by Lorraine Ellis on the new draft guidance. This Guest Commentary by Judith Lynn, continues the discussion about the new draft guidance. She looks at FDA Warning Letters in developing her review and analysis.

Guest Commentary: A Risk-Based Approach To Monitoring

I reviewed the Recent Draft Guidance From FDA- A Risk-Based Approach To Monitoring with several information points in mind:

• Warning letters from FDA, including the JNJ /ICON letter of 8/10/09
• My own experiences reviewing Clinical Study Reports, conducting TMF review and mock audits
• FDA Compliance Program Guidance Manual 7348.811, Clinical Investigators

I try to view the instruction as meant to be helpful rather than another obstacle to overcome. I found that much of the draft guidance centers on managing your study, having a sampling plan, and ensuring quality. FDA mentions that both good protocol and CRF design is critically important, as well as having a monitoring plan that takes into account the specific study, and sponsors prior experience with the investigational product.

Onsite monitoring:

FDA risk based monitoring guidance

Seriously Ill or Vulnerable Populations

I am not convinced that onsite monitoring will go away. The sponsor obligation is to ensure the protection of human subjects, that sites conduct trials appropriately, and the data is auditable and accurate. Note the point in the draft guidance under section IV/ C, Factors to consider when developing a monitoring plan: that “a population that is seriously ill and/or vulnerable may require more intensive on-site monitoring to be sure appropriate protection is being provided”. This point speaks volumes as to the value FDA places in onsite monitoring.

Early phase monitoring:

The guidance states “For a product that has either a significant safety concern or for which there is no prior experience in humans, may require more intensive monitoring to ensure appropriate investigator oversight.” It is interesting that FDA specifically encourages sponsors to be onsite in earlier phase studies, when the Agency does not typically send their own investigators- remember, they investigate either for cause or pre-approval.

In my experience with both bioavailability and first in man studies, the value of being on-site to observe unexpected safety and protocol issues, and make immediate decisions regarding study conduct, has been critical. Examples:

• safety issues a healthy subject (recent army recruit) collapsed at a blood draw (was excluded); a site had urine/blood test machine not work and had to test offsite, affecting dosing times/schedules
• dose issues, a nasal sprayer malfunctioned for an intranasal product; patches expected to be study for 12-24 hours fell off almost immediately

Electronic Data

risk based monitoring FDA guidance

Electronic Case Report Forms

Using electronic CRFs is a great boon to the industry. It gives almost instant access to data that used to take months to enter, review, check for consistency and plausibility.

Data Checks that used to come only at the end of a study are available throughout: such as missing forms; out of window visits; other inconsistencies. Immediate data availability can be used to track study progress, investigator compliance (with visits, data entry, inclusion/exclusion), and detect possible troublesome data fields/labels for a single site or throughout a protocol. However, only the data entered is available for central review (remote).

Use data to identify anomalies:

FDA risk based monitoring guidance

Questions Raised During Data Review

During an audit for a sponsor preparing for an FDA inspection, I focused on 2 critical efficacy evaluations (a 20 minute physician evaluation and MRI scan, done at select study visits). I requested data management to calculate the number of procedures performed on the same day at a specific site. I found it very interesting when data management responded:

• 22 physician evaluations were performed on a single day (by the same physician)
• 15 MRI scans were performed on one day.

None of the monitoring visit reports mentioned this kind of scheduling, the requirements for calibrating MRI machines, or whether there was more than 1 machine at a site.

It may be worthwhile to spend more time during the study reviewing available study data. You may need to create customized reports to follow the metrics on your study. Consider the value of team review rather than individual review, in order to understand what your data may be indicating.

FDA warning letters often include observations that may be found during onsite monitoring:

fda

FDA Warning Letters

• Problems with original signatures on informed consent documents. Informed consent documents are not usually submitted to sponsors/monitors, but are reviewed during onsite visits.
• Non-serious adverse events were present in source documents that were not reported to the sponsor. Without onsite review, the sponsor cannot know what is missing.
• Inadequate records, including remarks regarding inappropriate delegation (unqualified person performing procedure or not signed/dated by investigator). Many sites around the world have paper records, and without onsite review, the sponsor cannot be aware of inadequacies.
• Inadequate accountability of the test article.

Monitoring plan considerations:

You may decide to reduce the number of onsite visits. Do this wisely. Ideally the monitoring plan is another tool that helps confirm the validity of your study data. Have your monitors perform activities onsite that cannot be performed remotely.
Source data: Often, only limited source data is available remotely for centralized review.

Finally, remember what the FDA is instructing their inspectors to do, and develop your plan in anticipation. The FDA inspection manual requires inspectors to:

• review logs of onsite monitoring visits
• describe the investigators source documents for legibility and completeness
• review the informed consent process.

Ideally the sponsor will not be surprised what is found when a Regulatory agency goes to the study site.

Judith Lynn, Pharmaceutical Consultant, September 2011

Read the Draft Guidance Document

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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

The Federal Register Docket Number is FDA-2011-D-0597

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Pacific Regional Chapter SQA Fall Training 10-11 November at Allergan in Irvine, CA. The training will feature a debate which should be an interesting development in training workshops: Debi Garvin, MS, RQAP-GLP and Paula Parsons: Debate: The role of CAPA in a GLP environment.

PRCSQA Fall Training

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

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Training Opportunity:

training GxP

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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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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FDA vs. Dr. Oz: Should you be drinking apple juice? Television personality Dr. Oz says that there are dangerous levels of arsenic in apple juice. The FDA disagrees. They point out that the tests Dr. Oz conducts are for total arsenic, inorganic and organic, and only inorganic arsenic represents a danger to public health. Read the FDA press release for a detailed explanation.

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On The Blogroll: PharmTech Talk discusses the Top Ten FDA 483 Observations for drug GMP inspections. Angie Drakulich reports that Numero Uno concerns Quality Control Units (QCUs).

My Perspective by Kathryn Davis, Clinical Development. In this new blog on WordPress Kathryn Davis discusses relevant issues including social media, GCP, and recruiting minorities in clinical trials.

The Dark Daily Laboratory and Pathology News

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

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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.

GxP Perspectives LinkedIn Group

GxP Perspectives on twitter: @GxPPerspectives

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Please comment on the new draft guidance on Risk-Based Monitoring.


FDA Releases Draft Guidance for Monitoring Clinical Trials

September 4, 2011

FDA releases draft guidance document for monitoring clinical trials

FDA Draft Guidance Offers New Methods of Monitoring Clinical Trials

At long last, FDA has released a new draft guidance document for monitoring clinical trials. The previous FDA guidance document, Guideline for Monitoring Clinical Investigations (1988/1998) was withdrawn earlier this year. The new draft guidance document, FDA Guidance for Industry- Oversight of Clinical Investigations– A Risk-Based Approach (August 2011), discusses the changes in the way clinical trials are conducted and new methods of monitoring clinical trials. There is a 90-day comment period where members of industry, professional organizations, and the public can submit written commments to the agency for review and consideration.

In this Guest Commentary veteran monitoring specialist Lorraine Ellis gives her perspective on the new draft guidance for monitoring clinical trials.

Guest Commentary by Lorraine D. Ellis, MS, MBA

When I started monitoring, the Investigators completed CRFs from the source documents and there were few Clinical Research Coordinators (CRCs). Usually an office nurse or staff member would complete the forms when they had “free” time. Three decades later, sites, studies, and monitoring have changed significantly. Investigator sites must have significant study infrastructure (SOPs and facilities, etc) and trained/experienced staff to complete the complex trials of the 21st century. So it is significant that the 1988 Guidance document has been retired and the new guidance on monitoring describes FDA’s view on applying 21st century technology and methods to monitoring.

There are several key advances in this guidance. The guidance describes the term “centralized monitoring” for the many practices of using technology to review data off-site. This term and other FDA comments describe using “off-site” monitoring as one of the acceptable methods of monitoring data quality and study conduct. This guidance will intensify the discussions of “why do we need monitoring every 4 to 6 weeks with 100% source document verification” and “what is the best monitoring procedure for this study”. Also, FDA outlines more detailed monitoring plans as the risk based approach requires that monitoring approaches should be tailored to the trial.

clinical trial monitoring fda guidance document

Poorly Designed Protocols, CRFs, or Trial Instructions

FDA suggests a multi-factor approach to ensure data integrity, compliance and patient protection since there are many trial factors that can affect these trial elements besides monitoring. For example, poorly designed protocols, CRFs, or trial instructions could cause fatal trial errors despite extensive monitoring. Inadequate, incomplete or poor training of all involved in the trial, Investigators, staff, monitors etc., could also decrease study quality. The guidance encourages using various methods of study conduct review to assess these study elements as well as data quality.

The second half of the guidance provides information on monitoring plans and their expected content. Currently monitoring plan content and quality vary among Sponsors so this detailed section should increase monitoring plan quality and detail as it describes methods appropriate to the study. Since this guidance promotes custom monitoring plans based on variables of the study such as scope and complexity, these sections will assist Sponsors in designing and implementing those monitoring practices appropriate to the study.

FDA clinical trials guidance

"Greater Reliance on Centralized Monitoring"

One sentence will probably be surprising to some veteran monitors and Sponsors. “FDA encourages greater reliance on centralized monitoring practices than has been the case historically, with correspondingly less emphasis on on-site monitoring”. Many Sponsors that have instituted EDC and other technologies for data collection/review, have not decreased on-site monitoring time they continue to rely on the “gold standard” of visits every 4 to 6 weeks and 100% SDV. FDA does advise that at least one on-site monitoring visit should be done to ensure processes and procedures are in place at the site to ensure data quality. FDA continues that to use centralized monitoring properly, Sponsors need to develop methods and standard operating procedures so that site records, data entry, and data reporting follow well-defined procedures.

FDA guidance on clinical trials monitoring

Risk-Based Approach

FDA recommends that the monitoring plan is developed based on a risk assessment of the study complexity, study endpoints, disease complexity, geography, Investigator experience, EDC capabilities, Investigational product safety, study stage and quantity of data. After risk assessment, the Sponsor prepares a tailored monitoring plan for each study that will address that risk and outlines the multi-faceted approach to the trial. The plan, that includes monitoring procedures, monitoring responsibilities, and trial requirements, should be in sufficient detail so monitors and others involved can carry out their respective tasks correctly.

The plan should also include: monitoring methods, communication of monitoring findings, resolution of issues, training topics, training evaluation, and monitoring plan amendments.
It will be interesting to read the comments sent to FDA in the next 90 days. Some Sponsors will say “it’s about time” monitoring will be optimizing 21st century technology. Others may struggle with the changing of the “gold standard” of monitoring. In any case, this guidance may be the catalyst the industry needs to optimize monitoring methods and effectiveness.

FDA Guidance for Industry: Oversight of Clinical Investigations– A Risk-Based Approach

Visit Lorraine’s Website

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How to comment: 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

The Federal Register Docket Number is FDA-2011-D-0597

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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 LinkedIn group (below).

Please take a short 3-question survey to help GxP Perspectives improve! Survey begins 22 SEP 2011

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On the Blogroll: Chromosome which features an excellent post on, “The Site’s Side,” by Jae Chung, founder of goBalto, Inc., located in San Francisco. The post discusses some of the problems clinical sites face with monitors.

On The Blogroll: On Biostatistics and Clinical Trials– Finally a blog on biostatistics that I can almost read:) It is written by Dr. Deng, 邓春勤 A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development Industry
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clinical trials FDA monitoring guidanceThere have been some great comments on the GxP Perspectives LinkedIn group on the draft guidance document. 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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The FDA, Center for Drug Evaluation and Research (CDER) is announcing an industry workshop entitled ‘‘CDER Small Business Assistance – Clinical Trials and Electronic Submissions.” This two day event will be held in two California locations consecutively. The first workshop will be held in Los Angeles, CA, on September 26-27, 2011, followed by a second in San Francisco, CA, on September 28-29, 2011.
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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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GxP Perspectives has returned to twitter: @GxPPerspectives

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