FDA Form 1572 and Information Sheet Guidance May 2010

The FDA form 1572 is a form that must be completed by clinical investigators worldwide prior to their participation in FDA-regulated clinical trials. Many clinical investigators, sponsor pharmaceutical companies and monitors still may not appreciate the growing complexities involved in completing the mandatory form, implications
of non-compliance or clinical submission. Last year, FDA issued numerous warning letters due to failure to complete and/or failure to file. Experienced clinical investigators continue to struggle with 1572 issues pertaining to:

• satellite clinical sites
• dispersion of study functions
• qualifications
• sub-investigator
• co-investigator
• legal/regulatory implications
• legal contract considerations
• appropriate expert standards
• country-specific uses
• collection of source documentations and process.

Offered at http://www.danteresources.com/ are the following pdf files for your download, information and use. Just released and published in May 2010, FDA offers a comprehensive, 17 page guidance on process, procedure, quality and otherwise for:

• FDA Form 1572 - Statement of Investigators - Title 21 CFR Part 312.53(c)
• FDA Form 1572 Information Sheet Guidance for Sponsors, Clinical Investigators and IRBs and Frequently Asked Questions.

Available at druginfo@fda.hhs.gov. Published May 2010, US Department of Health and Human Services, FDA, Office of GCP, CDER, CBER, Procedural Recommendations.

Who should read the guidance and understand the form? Clinical trials monitors, clinical investigators, site staff, research center compliance officers, CRC, CRA, QC, QA, IRB, CSTM, Regulatory Affairs Staff, Pharmaceutical Sponsors. Form FDA 1572 issues will trigger a Refusal to File, RTF as well.

FDA Action and Enforcement Involving Medical Product Misbranding

FDA closely monitors the development, performance, safety and efficacy of drugs, diagnostics, biologics, personalized, combination, traditional, proteomics, genomics and delivery device systems as well as investigating illegal actions involving Internet "website" misbranding of drugs, claims, marketing, sales initiatives, advertising and otherwise. In 2009, for example, FDA coordinated a week long, global effort to uncover such illegal activities. Via the IIWA, FDA issued at least 22 warning letters pertaining to "website" illegal claim and misbranding activities involving:

• service providers
• domain name registrars
• selling products violators
• prescription drugs
• pharmacies
• counterfeit drugs
• contaminated drugs
• expired drugs
• adulterated drugs
• unapproved drugs
• active ingredient inconsistencies
• change of formulation
• batch to batch, lot to lot deviations
• CMC changes
• counterfeit claims
• altered medical devices.

Divisions at FDA working in conjunction with FDA's OCI, Office of Criminal Investigation, CDER, Center for Drug Evaluation and Research, Office of Regulatory Affairs, targeted 136 websites who were actively and knowingly engaged in the marketing and sale of unapproved and/or misbranded medical products and drugs. The penalties for such illegal actions are civil and criminal, resulting in imprisonment, fines, immediate company closure, loss of operating licenses and otherwise. The violations trigger immediate loss of service provider and domain name registrars, revocation, suspension and termination. Seizure and elimination of the illegal supply chain, drug, medical products and devices are immediate. The protection is enforced due to the medical risk and danger to patients and consumers trusting false, misleading, misbranded, illegal claims for profit.

The initiative was sponsored by the ICPO, International Criminal Police Organization, the World Health Organization's International Medical Products Anti-Counterfeiting Task Force, the Permanent Forum on International Pharmaceutical Crime and national health and law enforcement agencies from 24 participating countries. Immigration, Customs, Border Protection, US Postal and other government worldwide agencies were involved in the week long effort to curb civil and criminal "misbranding" activities.

Information pertaining to the warning letters issued by FDA pertaining to the information cited above may be found on fda.gov.

Monitor the quality, consistency, accuracy pertaining to branding and labels, claims. Adhere to agency compliance and meet regulatory requirements for all phases of medical product development, preclinical, CMC, clinical, application, implementation, surveillance, clinical submission, pre-approval, approval, post-approval commitments, advertising, marketing, branding, label requirements, claim substantiation and sales.

QC, QC and QC again. Monitor, monitor and monitor again. contactus@danteresources.com.

Proteomic Discovery, Development, Clinical Submission - From Peptides to Biomarkers

Among new, emerging discoveries, personalized medicine, combination products, delivery systems, translational medicine is the discovery of peptide biomarkers, proteomics. Biomarker discovery is a dynamic area of R&D which is born from natural, native physiological and pathological processes in biological systems. The field of biomarker discovery and development - identification, classification, R&D, clinical development phase, transition and validation is currently under debate. A number of groups such as NIH, National Institute of Health Biomarker Definitions Working Group, Divisions at FDA and other regulatory agencies worldwide are in the process of establishing set criteria for proteomic biomarker development.

There are 3 types of Biomarkers:

• Prognostic: capable of providing information on clinical outcome at the time of diagnosis, independent of therapy
• Predictive: capable of providing information on the likelihood of response to a given therapeutic modality
• Screening: capable of providing information on clinical diagnosis in the general population.

The developmental phases are commonly categorized as Discovery, Transition and Validation.

Estimated timelines for the development of a proteomic biomarker (total duration = 48 months) is provided in months:

• Discovery 14
• Prototype Assay Development 5
• Pre-Validation of Assay 5
• Assay Development 7
• Clinical Validation 17.
• Clinical Validation includes, 5 phases of development - preclinical, Phase 1,2,3,4.
• The number of samples that must be collected and tested from discovery through validation into application and implementation increase in size in late phase development. Preclinical, POC, Proof of Concept samples collected and tested are usually small in number in discovery = 10, reaching hundreds in the validation stage, transitioning to thousands by the time of application to FDA and implementation.

Regardless of the type, a biomarker must demonstrate, under routine implementation methodologies and conditions of use how the marker impacts clinical management of a patient with life-threatening or terminal disease, either by improving patient outcome or QoL, Quality of Life or by lowering cost and time of patient care.

The quality, accuracy, reproducibility, consistency and integrity of data must be of high level and must be quality controlled, processed and assured. Quality management plans, SOPs, WIs, GCP, GLP, GMP and otherwise must be developed and meet compliance quality standards. All plans, procedures and processes must be developed in accordance with FDA regulatory requirements, guidance and guidelines for the year of the application/implementation. contactus@danteresources.com, danteresources@yahoo.com.

Personalized Medicine on the Horizon

Personalized medicine is a broad term that covers a wide variety of therapeutic approaches which include drug/diagnostic combination products arising from discoveries in areas of pharmacogenomics, pharmacogenetics and genetic expression. The largest number of personalized medicine products available is for oncology. However, personalized medicine is already being applied to many other different disease indications. Product development is promising in disease conditions which include autism, autoimmune disease, cardiovascular, CNS disorders, HIV infection, osteoarthritis, osteoporosis, pain, diabetes, Lupus, Crohn, Renaud and others.

Personalized medicine, combination products include the identification of biomarkers and validation platforms. Validation new product platforms and test methods are noted in areas of analytical validation, clinical validation, regulatory validation, compliance validation, validation of clinical utility, validation of benefit.

Monitor, manage, QA, QC and review emerging "cutting edge" data and data concepts. Regulatory scrutiny promises to be challenging in the emerging field of personalized medicine. Data and documentation must be of high quality. Clinical study protocol and design is rigorous and difficult, but rewarding with promising statistically significant and clinically meaningful patient results and benefits. FDA and global regulatory agencies require adherence to quality procedures, processes, data collection, entry, management, reporting, analysis and regulatory, clinical submission. Data must follow industry and regulatory standards according to CFR, GCP, GLP, QMP, DMP, QC, SOPs, WIs and otherwise.

As with all emerging science and clinical R&D, companies participating in a new area of therapeutics face a number of challenging issues, strategic, logistical, tactical, hypothetical and theoretical. Pharmaceutical and diagnostic companies must come together in a rapidly changing field of medicine from different segments of the market, traditional and "cutting edge" and come to a common understanding and "working" approach and must interact with each other. R&D, product development and regulatory clinical submission processes and procedures, formats and otherwise must be managed by experts, statisticians, data managers, safety and efficacy review boards and opinion leaders. Seek experts, contact danteresources.com, danteresources@yahoo.com.

Drug/Diagnostic Combinations - Personalized Medicine

Current widespread interest, industry, pharmaceutical, device, diagnostic, physician, patient and FDA is now focused on the development of drug/diagnostic combinations, drugs used to treat patients and diagnostic platforms that can provide information about how a patient may respond to treatment with that drug. The combination of drug (Rx) and diagnostic (Dx) is termed personalized medicine. The combinations are numerous and smart.

The personalized medicine approach provides numerous benefits for pharmaceutical and diagnostic companies, but most importantly, to the patient for several reasons. Most drugs are developed in accordance with the traditional development approach, Phase 1,2,3 clinical studies. Patients on clinical trial, must pass strict eligibility criteria to be enrolled and randomized to study treatment drug. Patients are informed of the study protocol design and experimental tests of the clinical trial. Patients are usually allowed participation from 18-65 years of age. Medical history is taken to assure the presence and diagnosis of disease or condition. Patient disease or condition severity is determined by scales, blood, urine, physical exam, EKG, baseline testing parameters. Patients with poorly defined underlying disease or complicated medical histories are still grouped in one category for treatment.

Much data is collected to ensure patient safety and patient well being on clinical trial. However, patients still experience adverse reactions, sometimes severe. Some patients respond to treatment drug and some patients derive no benefit from the treatment drug. The result of the traditional approach to drug development is that not all drugs work equally well in all patients. There are many factors that may affect how a patient may respond to a particular drug. Factors that may affect drug performance or patient risk/benefit, for examples are age, diet, environmental factors, psychological and physiological factors, genetic make-up of the patient, genetic changes via time and otherwise.

Therefore, it is not surprising that there is growing interest in the identification of methods and factors to determine:

1. which patients will respond well to a particular therapy
2. which patients are likely not to benefit from therapy
3. which patients are likely to experience adverse reactions and side effects caused by the therapy.

Hence the advancement of drug/diagnostic combinations or personalized medicine for patients.

Whether the approach to patient therapy is traditional or personalized medicine, quality data and documentation is mandatory. QC early in the planning stages of drug development plans and diagnostic test platforms. Contact http://www.danteresources.com/.

What is "STED"? Is STED Analogous to FDA's CTD?

STED is the Summary Technical Document format preferred by FDA for international medical device regulatory, clinical submissions. STED is a global pilot, voluntary program for PMA and 510(k) applications. Proposed STED guidelines were developed in the last decade by the Global Harmonization Task Force (GHTF) composed of 5 participating country members. GHTF encourages submitters of medical device applications to participate in this ongoing pilot program to ensure conformity across government regulatory agencies. Participating regulatory agencies who promote international harmonization via STED are the US, Australia, Canada, the European Union and Japan.

Proposed STED guidelines seek to ensure global documentation format conformity pertaining to safety and performance of medical device products. STED , in principle, is similar to the acknowledged and accepted CTD, Common Technical Document, which ensures documentation and format conformity across international country-specific drug regulatory, clinical submissions.

CDRH encourages medical device manufacturer participation in the STED Pilot Program. Data quality is expected to be high level, accurate, concise, quality controlled and quality assured. Pertaining to individual and simultaneous country-specific medical device filing(s), PMA or 510(k), outsource to expert regulatory, clinical consultants to ensure data accuracy, documentation and format consistency. To ensure ROI and filing success with no RTF, Refusal to File, seek QC experts. Contact http://www.danteresources.com/.

Off-Protocol New Experimental Treatments

Frequently asked by a clinical investigator and/or a patient is how to get information pertaining to "Off-Protocol" experimental, new treatments outside of clinical trial? There are a number of procedures to follow that will allow consent for clinical investigators and patients to obtain new off-protocol experimental treatments. While it is not true that you may always or even eventually get off-protocol treatments, the possibility if not limited to treatments which involve only FDA approved drugs. Off-protocol treatments may involve promising new drugs which have not yet been approved by FDA or other regulatory agencies worldwide.

Off-protocol, out of clinical trial treatments are not recommended. Even if you can get a treatment outside a clinical trial, that does not mean you should follow this type of practice. Indeed for many reasons, reasons pertaining to patient safety and quality control, off-protocol treatments are not advised. If you can find a treatment on clinical trial, I strongly recommend this type of practical participation for the patient. Clinical trial protocols are governed with regulations, guidance and FDA GCP, Good Clinical Practice to ensure patient safety and data quality management.

If an off-protocol treatment is pursued, there are usually considerable reasons for selecting treatment outside of clinical trial.

• There might not be an open clinical trial available.
• You might not qualify for the clinical trial.
• The clinical trial is randomized and "blinded" and you need active drug vs the possibility of being randomized to a placebo treatment arm.
• Travel to the clinical trial site is difficult, although usually worked out with the clinical site coordinator whenever possible.
• Insurance may cover the off-protocol treatment, and sometimes the reverse is true. This seems to be case-dependent.
• Life threatening situations.
• Terminal illness.

Let me stress again that it is not my recommendation to seek off-protocol treatments. It is strongly recommenced to seek well controlled clinical trials that adhere to GCP and are governed by FDA guidance to ensure patient safety.

In few instances, off-protocol, outside of clinical trial treatment may make sense. Risk and benefit considerations must be fully investigated before any decisions are made by the patient, by the physician, clinic or otherwise. Quality and GCP must always be followed with patients in general, even with off-protocol treatments, however, it is difficult to monitor, manage and enforce.