Expert Reaction to a Study Looking at Caffeine and Pregnancy

A study, published in BMJ Evidence Based Medicine, looked at caffeine use and pregnancy.

At Science Media Center, Dr. Adam Jacobs, Associate Director of Biostatistics, Premier Research, said:

“I note the author has published 2 books on the dangers of coffee which in my opinion should have been included in declarations of interest for the journal article.

“One of the factors mentioned as a strength of the paper is that the meta-analyses had consistent results. It seems likely that the meta analyses are summarizing mostly the same primary studies, so that consistency is hardly surprising. If the primary studies are affected by biases and confounding, then those biases and confounding are going to be consistently brought through into the meta-analysis.

“There are some obvious potential confounders here. Given that pregnant women have been advised to avoid excessive caffeine consumption for at least the last 40 years, you might expect that women who drink coffee during pregnancy are generally less likely to follow health advice, and possibly in some ways which are quite hard to measure. Even if obvious confounders such as smoking status are taken into account, more subtle confounders may still have affected the analysis and make it hard to be sure that any observed associations with caffeine use are causal.

“There is also the question of publication bias. In general, null studies are less likely to be published than studies with positive results, so it’s possible that there have been other, unpublished, studies showing that caffeine has no effect on pregnancy outcomes. This is not addressed in the paper at all.

“Finally, I note that the paper is a narrative review, which is generally less reliable than a systematic review.

“Overall, I think if I were a pregnant woman, I don’t think this paper would make me overly concerned about drinking the occasional cup of coffee.”

Why ePROs Are Quickly Becoming a Key Source for Greater Patient Engagement

With the need to incorporate remote ways of working and interacting with study participants, sponsors and contract research organizations (CROs) have turned to technology for critical study activities ranging from patient consent and consultation to site monitoring. A particular instance of increased technology uptake has been in the area of patient-reported outcome (PRO) data collected by electronic methods, known as electronic PRO (ePRO) data.

Background

The U.S. Food and Drug Administration (FDA) defines a PRO as “any report of the status of patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.”1 Historically, PRO data has been used as an adjunct to primary data in the context of clinical trials. However, due in part to the emergence of the COVID-19 pandemic, sponsors have increased their reliance on PRO data in order to maintain trial continuity. In particular, the need to gather data remotely has catapulted ePRO data to the forefront.

Benefits of ePROs

Using ePRO data can help maintain clinical trial integrity and, even outside the context of COVID-19, will continue to be a valuable adjunct data collection tool for studies that aim to capture information about the patient experience.

ePROs are designed to optimize the objectivity of inherently subjective data. Compared to paper-based PROs, ePROs offer a number of potential advantages, such as:

Click Here to read more at PM360

Neonatal Research Insights: Conducting Clinical Trials in the Smallest Patients

Despite the passage of various legislative initiatives aimed at increasing the frequency and quality of pediatric clinical trials, neonates continue to be treated with medicines that have not been studied or approved in this population.¹ Historically, sponsors may have felt that the ethical and logistical challenges limited the opportunities for neonatal research. Our experience has been that, with appropriate planning, it is possible to conduct high-quality research in these smallest of patients and address the unmet need for approved treatments for neonatal-specific conditions.

In this article, we explore key factors to consider when designing and conducting neonatal clinical trials:

Adapt the study to the characteristics of this young, vulnerable population and their families. It is critical for sponsors to take into account the specific needs of newborn babies and their families when developing approaches for study design and recruitment. For example, careful consideration should be given to the informed consent process, as parents or guardians will likely be asked to give consent amidst the stress surrounding the birth of a sick baby. Continuous consent, which allows for repeated discussions and opportunities to confirm or withdraw consent, is not only a best practice, but also a regulatory requirement for pediatric studies in the EU.²
Engage with stakeholders early and often. As with other segments of the pediatric population, neonates are not able to advocate for themselves. Consequently, the views of parents must be considered when developing the research agenda. It is also advisable for sponsors to engage with clinicians, investigators, and patient advocacy groups for their input, even before discussing development plans with regulatory agencies.
Respect the fast-paced, high-intensity culture of the neonatal intensive care unit (NICU). NICUs typically operate under strict processes and procedures, which may limit adaptation to study protocols, so it is important for sponsors to understand existing workflows and assess their potential impact on a trial. Another factor to consider is the staff involved in the trial, which will likely include both study-specific and NICU staff. It may be a good idea to limit the study-related involvement of the NICU staff to only those activities that cannot be performed by study staff.
Plan for long-term follow-up. In many cases, follow-up over three to five years may be needed to evaluate the long-term effects of medicines in neonates. In addition to funding, this long-term follow-up requires development of strategies to stay in touch with families after their initial involvement and to keep them involved.
Monitor the neonatal trial landscape for best practices and standardized assessments. Organizations such as the International Neonatal Consortium (INC) are focused on forging a standardized, harmonized regulatory path for evaluating the safety and effectiveness of neonatal therapies. Recently, the INC developed a neonatal AE severity scale to help standardize safety reporting across trials. Incorporating best practices and standardized, validated assessments can simplify protocols and reduce both documentation and staff burden in neonatal trials.

To take a deeper dive into the nuances of neonatal studies, download our white paper Addressing a Critical Unmet Need: Considerations for Designing and Conducting Neonatal Clinical Trials.

¹ Costa HTML, Costa TX, Martins RR, Oliveira AG. Use of off-label and unlicensed medicines in neonatal intensive care. PLoS ONE. 2018;13:e0204427.

² European Medicines Agency. Ethical Considerations for Clinical Trials on Medicinal Products Conducted With the Paediatric Population, 2008. Available at https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/ethical_considerations_en.pdf.

PM360 – Leveraging Emergency Use Authorizations to Bring COVID-19 Products to Market

With the emergence of the COVID-19 crisis, the scientific and medical communities have been tasked with bringing diagnostic and treatment modalities to patients in an expedited but safe manner. To help address this critical need, the Secretary of the U.S. Department of Health and Human Services (HHS) has declared a number of Emergency Use Authorizations (EUAs), which allow the FDA to help strengthen public health protections against the novel coronavirus threat by facilitating the availability and use of necessary medical countermeasures during this global health crisis.

What is an Emergency Use Authorization (EUA)?

EUAs are not unique to the COVID-19 pandemic. Under section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), when the HHS has declared an emergency, the FDA Commissioner has the authority to allow unapproved medical products or unapproved uses of approved medical products to be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, and nuclear (CBRN) threats when there are no adequate, approved, and available alternatives…

Click here to read more at PM360.

Med Ad News – Optimizing Early Oncology Studies Through Adaptive Trial Designs

Despite advances in technology and our understanding of the genetic and molecular underpinnings of cancer, making a meaningful impact on the survival and quality of life of patients with cancer remains a significant challenge. In fact, a recent review revealed that, among 59 cancer drugs approved by the U.S. Food and Drug Administration (FDA) based on the surrogate endpoint of response rate, only six showed overall survival benefit. A separate review of 93 cancer drug indications that were granted accelerated approval by the FDA showed that only 20 percent demonstrated improvement in overall survival in confirmatory trials, and that 20 percent showed improvement on the same surrogate measure used in both preapproval and confirmatory trials.

These findings underscore the importance of well-designed early phase oncology trials for establishing meaningful safety and efficacy signals for investigative cancer drugs. Historically, Phase 1 oncology trials have been thought of as studies for establishing the toxicity profile of novel therapeutic agents, with low clinical utility in terms of establishing efficacy. However, the traditional clinical trial paradigm involving three distinct trial phases has shifted with the advent of targeted therapies and immunotherapies, and we are seeing an increasing number of Phase 1 trials reporting preliminary response rates.

In this article, we discuss critical design considerations for early phase oncology studies and explore the use of adaptive designs for optimizing these studies to support later stage success.

The State of Cell Therapies in Dermatology

Skin contains essential stem cell populations and other cell types that are critical for renewing and maintaining its structural integrity and function.¹ Of the many types of skin stem cells that have been identified, epidermal stem cells — primarily keratinocyte stem cells — are recognized to play the key role in tissue repair and skin regeneration.² Most epidermal stem cells reside in the basal layer of the epidermis. These cells have been characterized as rare, infrequently dividing, and capable of generating the short-lived, rapidly dividing cells involved in regenerating the epidermis and repairing skin injury.²

In this article, we discuss the obstacles of developing cell therapies as well as the current status of cell-based therapies in dermatology.

Challenges in developing dermatology cell products

As with all cellular therapy products, the hurdles in developing cell products for skin repair include:²

Ability to ensure that the stem cells differentiate into the desired cell phenotype(s)
Identification of biomarkers that confirm cellular purity
Persistence of the cells in vivo
Understanding the potential impact of adjuvants and biomaterials on the cellular microenvironment and the immune response
Selection of an appropriate method for cell delivery or grafting
Assessment of the benefit-to-risk ratio compared to standard of care

Another wrinkle that is often overlooked in the development of cell therapies for dermatologic conditions is ethnic differences in skin composition, which may affect response to treatment.

Clinical research and applications of cell-based therapies in dermatology

Burns and wound healing. Approximately 1 million people sustain thermal injuries, or burns, each year in the U.S.³ Since the 1980s, cultured human keratinocyte clones have been used to treat patients with severe burns. There are currently several keratinocyte-based skin repair products on the market or in clinical trials, including autografts and suspensions:

Cultured epithelial autograft (CEA) sheets may also be used alone or in combination with skin autografts for wound closure. When used in combination, they may enhance the take of an autograft and improve both skin texture and scar quality.⁴ ⁵ ⁶
Cultured keratinocyte suspensions, when sprayed directly into a wound or used in combination with skin grafting, have been shown to accelerate epidermal wound healing.⁷

Rare diseases. Epidermal stem cells and genetically modified keratinocytes have also been studied in subtypes of epidermolysis bullosa (EB): ⁸ ⁹ ¹⁰

Researchers have successfully cultured autologous epidermal stems cells and modified them with a viral vector carrying a functional version of LAMB3, the mutated gene in junctional EB. These modified stem cells have then been grown into sheets of skin.¹¹
One clinical-stage biopharmaceutical company is studying the use of a retroviral vector to insert COLA7A1, the gene mutated in recessive dystrophic EB (RDEB), into keratinocytes. These genetically modified keratinocytes are then cultured into skin grafts.¹²
Another company is studying the use of a lentiviral vector to modify autologous fibroblasts, which can then be injected intradermally to treat RDEB.¹²

Other research and applications. More recently, somatic stem cells have received increased attention due to their potential to cross lineage boundaries under specific environmental conditions. Recent studies have shown that mesenchymal stem cells may be a promising therapeutic modality for wound healing, atopic dermatitis, and other inflammatory skin diseases, as well as autoimmune skin diseases such as graft versus host disease with skin manifestations and systemic lupus erythematosus.¹³ ¹⁴

Future considerations

Cell-based therapy is becoming an increasingly viable alternative or combination treatment for the management of burns and other wounds, but its clinical applications remain limited. Scientific and technical issues remain. For example, more clinical evidence is needed and the time required to generate CEAs may make it unsuitable for acute treatment of serious burn injuries. To realize the full potential of cell therapies in dermatology, we will need more well-designed trials to define efficacy and safety as well as technical advances that enable timely intervention.

¹ Li Z, Maitz P. Cell therapy for severe burn wound healing. Burns & Trauma. 2018;6:13.

² Chu GY, et al. Stem cell therapy on skin: Mechanisms, recent advances and drug reviewing issues. J Food Drug Anal. 2018;26:14-20.

³ Clark RA, Ghosh K, Tonnesen MG. Tissue engineering for cutaneous wounds. J Invest Dermatol. 2007;127:1018-1029.

⁴ Yim H, et al. Clinical study of cultured epithelial autografts in liquid suspension in severe burn patients. Burns. 2011;37(6):1067–71.

⁵ Soejima K, Nozaki M, Kobayashi M, Negishi N. Studies of surface microarchitecture using a hand-held video microscope in cases of cultured epithelial autografts. Ann Plast Surg. 1998;41(3):270–4.

⁶ Lee H. Outcomes of sprayed cultured epithelial autografts for full-thickness wounds: a single-centre experience. Burns. 2012;38(6):931–6.

⁷ Svensjö T, Yao F, Pomahac B, Eriksson E. Autologous keratinocyte suspensions accelerate epidermal wound healing in pigs. J Surg Res. 2001;99(2):211–21.

⁸ Uitto J, et al. Progress in epidermolysis bullosa research: toward treatment and cure. J Invest Dermatol. 2010;130:1778-1784.

⁹ Mavilio F, et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med 2006;12:1397-1402.

¹⁰ Hirsch T, et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. 2017;552:327-332.

¹¹ Arney K.. Change the genes to fix the skin. Nature; December 12, 2018. Available at https://www.nature.com/articles/d41586-018-07640-2. Accessed April 6, 2020.

¹² Armstrong M. Gene therapies go skin deep to tackle epidermolysis bullosa, Evaluate; March 11, 2019. Available at https://www.evaluate.com/vantage/articles/analysis/spotlight/gene-therapies-go-skin-deep-tackle-epidermolysis-bullosa. Accessed April 6, 2020.

¹³ Shin TH, Kim HS, Choi SW, Kang KS. Mesenchymal Stem Cell Therapy for Inflammatory Skin Diseases: Clinical Potential and Mode of Action. Int J Mol Sci. 2017;18(2).

¹⁴ Prodinger C, Reichelt J, Bauer JW, Laimer M. Current and future perspectives of stem cell therapy in dermatology. Ann Dermatol. 2017;29(6):667-687.

iPSP Considerations for Molecularly Targeted Cancer Drugs

With the passage of the Pediatric Research Equity Act (PREA) of 2003, drug manufacturers were required to submit an initial pediatric study plan (iPSP) prior to commencement of Phase 3 studies (or new drug application [NDA]/biologics license application [BLA] submission in the absence of a Phase 3 study) for studies involving a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration. The iPSP is expected to contain an assessment of safety and effectiveness of the investigational drug for the proposed indication in all relevant pediatric subpopulations. In certain situations, a deferral or waiver for conducting pediatric studies can be obtained.

Prior to the RACE for Children Act, the pediatric study plans for oncology drugs were generally proposals to request waivers for pediatric assessments because the adult cancer indications for which a drug was developed did not occur, or occurred only rarely, in pediatric patients, making pediatric studies impossible or highly impracticable. The RACE for Children Act amended PREA to require pediatric investigation of certain targeted cancer drugs based on molecular mechanisms of action rather than the clinical indication for original BLAs/NDAs submitted on or after August 18, 2020, unless a deferral or waiver is granted.

An iPSP for a molecularly targeted oncology drug should address the drug’s molecular target and its relevance to one or more cancers that occur in the pediatric population. An iPSP is expected to include the following elements:

Description of the cancer(s) in the pediatric population for which the drug warrants early evaluation
Overview of the drug product
Overview of planned extrapolation of effectiveness to the pediatric population
Planned request for drug-specific waivers and partial waivers with justification
Planned request for deferrals of pediatric studies
Tabular summary of proposed non-clinical and clinical studies
Age-appropriate formulation including details of existing/planned excipients
Non-clinical proof-of-concept studies (planned and completed)
Data to support clinical studies in pediatric patients
Planned pediatric clinical study or studies
Timeline of the pediatric development plan
Agreements for pediatric studies with other regulatory agencies

Our new white paper Understanding New FDA Guidance for Pediatric Oncology Studies: A Sponsor’s Guide to the FDA RACE for Children Act focuses on other considerations for developing an iPSP for a molecularly targeted cancer drug, including planned pediatric clinical studies, considerations for rare cancers, and early advice on pediatric development meetings, as well as conditions for obtaining planned waivers or deferrals. Click here to download.

5 Things to Know About the FDA RACE for Children Act

The Research to Accelerate Cures and Equity (RACE) for Children Act aims to improve and expand treatment options for pediatric cancer patients by mandating that all new adult oncology drugs also be tested in children when the molecular targets are relevant to a particular childhood cancer. Enacted August 18, 2017, as part of the Food and Drug Administration (FDA) Reauthorization Act (FDARA), it amends the Federal Food, Drug, and Cosmetic Act (FFDCA) to revise and extend the user-fee programs for drugs, medical devices, generic drugs, and biosimilar biological products and for other purposes.

Here are five things sponsors of pediatric oncology studies should know about the FDA RACE Act. To learn more about the legislation and the FDA’s accompanying draft guidance, download our white paper Understanding New FDA Guidance for Pediatric Oncology Studies: A Sponsor’s Guide to the FDA RACE for Children Act.

1. RACE sets new requirements for pediatric oncology studies starting this August.

RACE requires that any original new drug application or biologics license application submitted on or after August 18, 2020, for a new active ingredient must contain reports of molecularly targeted pediatric cancer investigations (unless a deferral or waiver of that requirement is granted) if the drug is:

Intended for the treatment of an adult cancer, and
Directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer.

2. The RACE Act expands upon previous legislation and policies designed to encourage pediatric drug development.

The Best Pharmaceuticals for Children Act (BPCA) of 2002 provides an incentive of additional marketing exclusivity to sponsors who voluntarily complete pediatric clinical studies outlined in a written request issued by the FDA, and the Pediatric Research Equity Act (PREA) of 2003 authorizes the agency to require drug manufacturers to complete studies in children for the same adult indications when the drugs are expected to be used in a substantial number of children.

3. The legislation comes as a response to a transformation of the paradigm of cancer drug development with molecularly targeted drugs.

Advances seen in the treatment of adult oncology indications have rarely been extended to development of pediatric cancer treatments. But extensive research has demonstrated that malignancies occurring in children and adolescents can harbor the same molecular abnormalities as those found in adult cancers, indicating that the new targeted oncology drugs may prove effective in treating pediatric patients with cancer, even if the adult cancer indication does not occur in the pediatric population.

4. RACE eliminates the orphan exemption for pediatric studies for cancer drugs directed at relevant molecular targets.

Under the PREA orphan exemption, PREA does not apply to any drug application for an indication for which orphan drug designation has been granted when that application would otherwise trigger PREA. However, the RACE requirement for pediatric investigation applies even if the adult cancer indication does not occur in the pediatric population and the drug is for an adult indication for which orphan designation has been granted.

5. The FDA maintains lists of both relevant and non-relevant molecular targets to provide further guidance to sponsors.

In collaboration with the government, academic and industry experts, and advocates, the FDA established, published, and updates two lists:

Relevant Molecular Targets: considered to be substantially relevant to the growth or progression of a pediatric cancer
Non-Relevant Molecular Targets That Warrant Waiver From Required Evaluation: considered not substantially relevant

The lists are a guide for sponsors as they consider development plans for new targeted drugs and early pediatric assessments in light of the amended PREA provisions. However, sponsors of molecularly targeted oncology drugs are encouraged to seek early advice from the FDA.The passage of FDARA is a significant milestone in promoting pediatric cancer drug development that is bound to have significant implications on how sponsors plan and prepare for NDA/BLA filing of molecularly targeted oncology drugs. To learn more, download our white paper Understanding New FDA Guidance for Pediatric Oncology Studies: A Sponsor’s Guide to the FDA RACE for Children Act today.

The State of Gene Therapy in Dermatology

When it comes to dermatologic conditions, gene therapy is still in its very early stages. However, we are seeing promising potential solutions for some rare genetic dermatology diseases, as well as ongoing research in more common skin conditions.

The success of gene-based therapies relies on three critical elements:¹

A well-defined disease gene
A therapeutic gene
An efficient gene delivery system, whether it is a viral or non-viral vector

In our first article, we reviewed gene transfer techniques and gene delivery systems that could potentially be used for treating dermatologic conditions. Now we turn our attention to the current state of gene therapy for dermatologic conditions.

Gene Therapy in Epidermolysis Bullosa

Currently, the greatest strides in dermatology gene therapy have been made in epidermolysis bullosa (EB). Affecting an estimated 1 in every 20,000 children born in the U.S., EB is a family of inherited blistering skin disorders associated with gene defects affecting gene expression of the basal epidermis. At least eighteen genes and 13 proteins responsible for the specific subtypes of EB have been characterized.² ³

There are three main subtypes of EB: EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB), each of which is caused by different mutations and affects different levels of the epidermis:

EBS is typically caused by dominant mutation in the genes encoding for keratin 5 or keratin 14, and is generally the mildest phenotype
JEB is attributable to recessive mutation in one of three genes (LAMA1, LAMB3, and LAMC2) encoding subunits of the laminin-332 protein, which binds the surface of the skin to the underlying layers⁴
DEB can be either recessive (RDEB) or dominant, and is attributable to mutation in COL7A1, the gene encoding type VII collagen

Gene therapies are being explored to address all three subtypes of EB. There are currently at least three companies investigating gene therapy approaches for RDEB in early phase clinical trials:⁵ ⁶

Krystal Biotech is studying a topical gel that uses a herpes simplex viral vector to deliver COLA7A1
Abeona Therapeutics is using a retroviral vector to insert the COLA7A1 into keratinocytes, which are then cultured into skin grafts
Fibrocell Science is utilizing a lentiviral vector to modify autologous fibroblasts, which are then injected intradermally

Significant clinical advances in gene therapy research have also been seen in JEB. In 2006, a group of researchers reported successful ex vivo gene therapy using genetically modified autologous skin grafts expressing LAMB3 in one patient with JEB.⁷ More recently, in 2015, these same researchers again cultured the epidermal stem cells of a patient and modified them with a viral vector carrying a functional version of LAMB3. These modified stem cells were grown into sheets of skin large enough to replace approximately 80% of the patient’s entire epidermis.^{4 NATURE} By 2017, the patient’s blisters had been replaced with smooth, fully functional skin. In an article published in Nature, the researchers demonstrated that this type of long-term grafting was only possible because the genetically modified stem cells were holocones, a rare type of stem cell that can self-renew indefinitely.⁸

Gene Therapy in Other Skin Diseases

Melanoma. There are currently multiple clinical trials in melanoma exploring various gene therapy approaches. These approaches range from genetically modified autologous lymphocytes and adenovirus-mediated interleukin-2 intralesional injections to genetically modified autologous T cells expressing T-cell receptors against a variety of tumor antigens.^{5 GORELL}

Other Genetic Skin Diseases. Gene therapy has also been studied in inherited skin disorders such as ichthyosis and the rare diseases pachyonychia congenita and xeroderma pigmentosum.⁹ ¹⁰ Krystal Biotech is currently conducting a phase 1/2 clinical trial of a topical gene therapy for TGM-1 deficient autosomal recessive congenital ichthyosis.¹¹

Wound Healing. Another area of gene therapy exploration is wound healing, a complex, multifactorial process. Animal studies of gene therapy for wound healing have focused on boosting growth factors, such as vascular endothelial growth factor and epidermal growth factor, which are known to assist with wound healing.¹²

The Promise of Gene Therapy

In addition to the millions of Americans living with dermatologic conditions, thousands of children are born every year with genetic skin disorders. With continuing advances in gene therapy, we may one day be able to prevent the formation of pathological skin lesions, rather than having to treat or cure them.

¹ Shaaban D, Neinaa Y. Gene therapy: Its applications in dermatology. GJDV. 2017;24(1).

² Marinkovich MP. Inherited epidermolysis bullosa. In: Fitzpatrick’s dermatology in general medicine (eds. Goldsmith LA, et al.), 2012, pp. 649-665. McGraw Hill, New York.

³ Has C, et al. Integrin a3 mutations with kidney, lung, and skin disease. N Engl J Med. 2012;366:1508-1514.

⁴ Nature. Change the genes to fix the skin. Available at https://www.nature.com/articles/d41586-018-07640-2. Accessed March 2, 2020.

⁵ ClinicalTrials.gov. Search for epidermolysis bullosa gene transfer, March 18, 2020.

⁶ Evaluate. Gene therapies go skin deep to tackle epidermolysis bullosa, March 11, 2019. Available at https://www.evaluate.com/vantage/articles/analysis/spotlight/gene-therapies-go-skin-deep-tackle-epidermolysis-bullosa. Accessed March 18, 2020.

⁷ Mavilio F, et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nature Med. 2006:12:1397-1402.

⁸ Hirsch T, et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. 2017;552:327-332.

⁹ Leachman S, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther. 2010;18:442-446.

¹⁰ Warrick E, et al. Preclinical corrective gene transfer in xeroderma pigmentosum human skin stem cells. Mol Ther. 2012;20:798-807.

¹¹ ClinicalTrials.gov. Search for ichthyosis gene therapy, March 18, 2020.

¹² Gorell E, et al. Gene Therapy for Skin Disease. Cold Spring Harb Perspect Med. 2014;4:49-51

Snapshot: A New Guidance Document Program From the FDA

As a regulatory affairs professional advising various stakeholders on the interpretation and implementation of guidance documents from the FDA, I can safely say that the task is challenging in the best of cases. FDA guidance documents have a tendency to be vague and difficult to decode. As experts, we are always debating about what the guidance is asking and how the contents are to be applied.

In a progressive effort to mitigate these long-standing concerns and bring a level of clarity to its guidance documents, the FDA has created a pilot program called “Guidance Snapshots.” Under this program, the FDA is releasing an initial set of guidance documents that will assist stakeholders in accelerating development. This “snapshot” is designed to highlight key aspects of a particular guidance and make the document more transparent. The snapshot will include the following list of items:

Link to the full guidance document
Explanation of why the guidance document is important
Educational background about the guidance topic
Link to the FDA docket for providing official comments to the Agency (for applicable draft guidance documents)
Drug development timeline for when to apply the guidance recommendations
Highlights from the guidance document
Guidance Recap Podcast that describes highlights and background of the guidance document explained directly from the authors
Twitter hashtags to create a platform for discussing views on the guidance

With such a new program, the FDA is careful to note that “Guidance Snapshots are not a substitute for the guidance document. Guidance Snapshots should not be used to make drug development decisions.”

So far, three snapshots have been released; two are on drug interactions with cytochrome P450 enzyme systems for new drugs during clinical and in vitro testing, and the third is on developing targeted therapies in low-frequency molecular subsets of a disease.

The industry hopes that FDA continues to modernize and partner on such initiatives by creating an environment that is transparent and collaborative. With the release of the Guidance Snapshot program, the agency is taking a step in the right direction. This move will certainly help stakeholders to bring key therapies to patients with a renewed sense of urgency.

Premier Research looks forward to continuing to assist our partners with the interpretation of FDA guidance documents and making sure that the information from suc

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