CRDP Certification Review

Certified Rare Disease Pharmacist (CRDP) Review

A Review Guide for the Certified Rare Disease Pharmacist (CRDP) Exam

Block 1: Foundations

ASO: Antisense Oligonucleotide

CBER: Center for Biologics Evaluation and Research

CDER: Center for Drug Evaluation and Research

CF: Cystic Fibrosis

CLIA: Clinical Laboratory Improvement Amendments

DMD: Duchenne Muscular Dystrophy

EAP: Expanded Access Program

ERT: Enzyme Replacement Therapy

FDA: Food and Drug Administration

GCP: Good Clinical Practice

HCPCS: Healthcare Common Procedure Coding System

ICER: Institute for Clinical and Economic Review

IND: Investigational New Drug

IRB: Institutional Review Board

LDT: Laboratory Developed Test

LSD: Lysosomal Storage Disorder

NIH: National Institutes of Health

NORD: National Organization for Rare Disorders

ODA: Orphan Drug Act

PA: Prior Authorization

PAG: Patient Advocacy Group

QoL: Quality of Life

REMS: Risk Evaluation and Mitigation Strategy

RWE: Real-World Evidence

siRNA: Small interfering RNA

SMA: Spinal Muscular Atrophy

SP: Specialty Pharmacy

SRT: Substrate Reduction Therapy

  • Definition of Rare Disease: In the U.S., a disease that affects fewer than 200,000 people. In Europe, a disease that affects fewer than 1 in 2,000 people. There are over 7,000 known rare diseases.
  • Core Role of the CRDP: To serve as a clinical expert and logistical coordinator for patients on complex, high-cost orphan drug therapies. This involves a blend of clinical management, operational excellence, and compassionate patient support.
  • High-Touch Model: Rare disease pharmacy operates on a "high-touch" care model, characterized by frequent and proactive communication with patients, caregivers, and providers to ensure optimal outcomes.
  • Orphan Drug Act (ODA) of 1983: The landmark U.S. legislation created to incentivize the development of drugs for rare diseases.
  • Key Incentives of the ODA:
    • 7-Year Market Exclusivity: The first sponsor to get FDA approval for an orphan drug for a specific indication gets 7 years of protection from competition.
    • Tax Credits: For qualified clinical trial expenses.
    • Waiver of FDA Fees: Including the expensive Prescription Drug User Fee Act (PDUFA) fees.
  • Other Relevant Legislation: Includes the 21st Century Cures Act, which created pathways to accelerate drug development, and various PDUFA reauthorizations that have refined the review process.
  • Prevalence vs. Incidence: Understanding the difference is key. Prevalence is the total number of cases at a point in time, while incidence is the number of new cases over a period of time. Rare diseases are defined by prevalence.
  • Genetics: Approximately 80% of rare diseases are genetic in origin, often caused by single-gene mutations.
  • Newborn Screening (NBS): State-based public health programs that screen newborns for a panel of treatable genetic conditions (e.g., CF, SMA). Early diagnosis through NBS is critical for improving outcomes.
  • The Diagnostic Odyssey: The long, frustrating path many patients take to get an accurate diagnosis. It can take an average of 5-7 years and involve seeing multiple specialists.
  • Impact on Patients & Families: The journey is often marked by misdiagnosis, financial strain, and significant emotional and psychological distress. The pharmacist must be empathetic to this lived experience.
  • Role of Genetic Testing: Advances in genetic testing, such as whole exome sequencing (WES), are helping to shorten the diagnostic odyssey for many patients.

Block 2: Drug Development & Access

  • Small Patient Populations: The biggest challenge. It is difficult to recruit enough patients for large, statistically powered randomized controlled trials (RCTs).
  • Alternative Trial Designs: This often necessitates the use of novel trial designs, such as single-arm studies (where all patients receive the drug), historical controls, or n-of-1 trials.
  • Surrogate Endpoints: Due to the long time it may take to see a clinical outcome, trials often use surrogate endpoints (e.g., a biomarker) that are reasonably likely to predict a clinical benefit.
  • Purpose: To speed the development and review of drugs for serious conditions and to fill an unmet medical need. Many orphan drugs qualify for these programs.
  • Key Programs:
    • Fast Track: Facilitates development and expedites review.
    • Breakthrough Therapy: For drugs showing substantial improvement over available therapy. Includes intensive FDA guidance.
    • Accelerated Approval: Allows for earlier approval based on a surrogate endpoint.
    • Priority Review: Reduces the FDA's review timeline from 10 months to 6 months.
  • Definition: A potential pathway for a patient with a serious or life-threatening condition to gain access to an investigational medical product outside of a clinical trial when no comparable or satisfactory alternative therapy options are available.
  • The Pharmacist's Role: The pharmacist is often involved in coordinating the complex process of an Expanded Access Program (EAP) request, which involves the physician, the drug manufacturer, and an IRB.
  • Critical Partners: PAGs (e.g., NORD, Global Genes, disease-specific groups like the CF Foundation) are essential partners in the rare disease ecosystem.
  • Key Functions: They provide support and education for patients, fund research, advocate for policy changes, and help drive drug development by creating patient registries and engaging with the FDA and manufacturers.
  • International Collaboration: Networks like Orphanet and the International Rare Diseases Research Consortium (IRDiRC) are critical for sharing data and advancing research across borders.
  • Varying Access: Access to orphan drugs varies significantly by country, depending on their national health system, regulatory approval process, and health technology assessment (HTA) decisions.

Block 3: Pharmacology & Therapeutics

  • Mechanism: For diseases caused by a missing or deficient enzyme (e.g., many Lysosomal Storage Disorders), ERT involves intravenously infusing a recombinant version of the functional enzyme.
  • Limitations: ERTs are palliative, not curative. They require lifelong, regular infusions and cannot cross the blood-brain barrier to treat neurological symptoms.
  • Mechanism: mAbs can be designed to target specific proteins involved in rare disease pathology, such as blocking an overactive pathway or inhibiting a specific complement protein (e.g., eculizumab for PNH and aHUS).
  • Mechanism: Unlike large-molecule biologics, these are oral small molecules. Chaperone therapies bind to a misfolded mutant protein, helping it to fold correctly and restoring partial function. Modulators, like those for CF, help a dysfunctional protein channel work better.
  • Mechanism: An alternative to ERT. Instead of replacing the missing enzyme, SRT uses a small molecule to partially block the production of the substrate that the enzyme would normally break down. This prevents the toxic accumulation of the substrate.
  • Mechanism: These therapies work at the RNA level to alter protein production. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) can be designed to bind to a specific mRNA molecule, either preventing its translation (gene silencing) or modifying how it is spliced (e.g., nusinersen for SMA).
  • The Curative Potential: The most exciting frontier. Gene therapies aim to provide a one-time, potentially curative treatment by correcting the root genetic cause of a disease. They are now approved for several rare conditions like SMA and certain hemoglobinopathies.
  • Pathophysiology: Caused by mutations in the CFTR gene, leading to dysfunctional chloride channels and thick, sticky mucus.
  • Therapies: A success story of precision medicine. CFTR modulators (e.g., Trikafta) are small molecules designed to correct the function of the specific mutant protein a patient has.
  • Pathophysiology: A group of ~50 genetic diseases (e.g., Gaucher, Pompe, Fabry) caused by defects in lysosomal enzymes, leading to the accumulation of waste products in cells.
  • Therapies: This class is the classic model for Enzyme Replacement Therapy (ERT) and, more recently, Substrate Reduction Therapy (SRT).
  • Pathophysiology: Caused by a mutation in the SMN1 gene, leading to the loss of motor neurons and progressive muscle weakness.
  • Therapies: Revolutionized by three different modalities: an RNA-based therapy (nusinersen, an ASO), a one-time gene replacement therapy (onasemnogene abeparvovec), and an oral small molecule (risdiplam).
  • Pathophysiology: Caused by mutations in the dystrophin gene, leading to a lack of functional dystrophin protein and progressive muscle degeneration.
  • Therapies: Include exon-skipping drugs (a form of RNA therapy) that aim to produce a truncated but partially functional dystrophin protein, as well as emerging gene therapies.

Block 4: Patient Management & Operations

  • Comprehensive Onboarding: A structured process for new patients that includes a benefit investigation, scheduling of initial training and infusions, and a thorough clinical assessment by the pharmacist.
  • Patient Education: Providing detailed, tailored education on the disease state, the specific drug, its administration, potential side effects, and the importance of adherence. This is an ongoing process, not a one-time event.
  • Barriers to Adherence: Include high cost, complex administration (e.g., infusions), high side effect burden, and treatment fatigue from lifelong therapy.
  • Pharmacist-Led Interventions: Proactive outreach calls, symptom management, coordination with home health nurses, and leveraging technology like mobile apps to support patients.
  • Infusion-Related Reactions (IRRs): A common risk with infused biologics. The pharmacist ensures appropriate pre-medication protocols are in place and that staff are trained to manage reactions.
  • Proactive Symptom Management: The pharmacist regularly follows up with patients to screen for and manage common side effects, helping to improve both adherence and quality of life.
  • Site of Care: Many orphan drugs are administered via home infusion. The pharmacist coordinates with the home infusion provider to ensure safe and effective administration.
  • Self-Injection Training: For subcutaneously administered drugs, the pharmacist or nurse provides comprehensive training to the patient or caregiver on proper injection technique, storage, and disposal.
  • Limited Distribution Drugs (LDDs): Most orphan drugs are not available through retail pharmacies. They are distributed through a limited network of accredited specialty pharmacies.
  • Accreditation: Specialty pharmacies that handle orphan drugs are typically accredited by organizations like URAC and ACHC, which set high standards for clinical management and operations.
  • Cold Chain Management: Most orphan drugs are biologics that require strict temperature control (typically 2-8°C) from the moment they leave the manufacturer until they are administered. The pharmacist must manage and document this "cold chain."
  • Product Handling: Understanding the specific handling requirements for each product, such as the need for special diluents, filters, or infusion bags, and protecting them from light or agitation.
  • A Critical Juncture: As treatments improve, many patients with pediatric-onset rare diseases are now surviving into adulthood. The transition from pediatric to adult care is a high-risk period.
  • Pharmacist's Role: The CRDP helps ensure a smooth transition by educating the adult care team, empowering the adolescent patient to take ownership of their care, and navigating changes in insurance coverage.
  • Team-Based Care: Rare disease is managed by a multidisciplinary team (physicians, nurses, genetic counselors, social workers, physical therapists). The pharmacist is a key member, acting as the medication expert and a central communication hub.
  • Purpose: Many orphan drugs have significant safety risks that require a Risk Evaluation and Mitigation Strategy (REMS) to ensure the benefits outweigh the risks.
  • Pharmacist's Responsibility: The pharmacist is responsible for executing the key components of the REMS, which may include patient enrollment, specific monitoring, and documenting safe-use conditions before dispensing.
  • Central Coordination Point: A "Hub" is a centralized service, often sponsored by the manufacturer, that helps manage the patient journey.
  • Hub Functions: Includes services like benefits investigation, prior authorization support, financial assistance coordination, and connecting patients with specialty pharmacies and nursing services. The CRDP works closely with these hubs.

Block 5: Reimbursement, Data & Tools

  • The Access Barrier: Securing insurance approval is often the first and most significant hurdle. The pharmacist assists the provider's office in compiling the necessary clinical documentation to submit a thorough prior authorization (PA).
  • A Complex Distinction: Determining whether an orphan drug will be covered under the medical benefit (as a physician-administered drug) or the pharmacy benefit (as a self-administered drug) is a critical step that dictates the entire reimbursement and delivery workflow.
  • Mitigating Financial Toxicity: Due to the extreme high cost, even patients with good insurance can face unaffordable out-of-pocket expenses. The pharmacist helps connect patients with manufacturer-sponsored copay programs and independent charitable foundations to mitigate this burden.
  • Post-Approval Data: Because orphan drugs are often approved based on small trials, collecting long-term Real-World Evidence (RWE) on their safety and effectiveness is critical.
  • Patient Registries: These are organized systems for collecting uniform data on a patient population. Pharmacists often play a role in enrolling patients and contributing data to these important research tools.

Functional Status Scales

Many rare disease trials use specific, validated scales to measure a patient's functional ability as a primary endpoint. Examples include the 6-Minute Walk Test (6MWT) for DMD or the CHOP INTEND scale for infants with SMA.

Quality of Life (QoL) Questionnaires

These are validated surveys used to measure the impact of the disease and treatment on a patient's overall well-being. Both general health surveys (e.g., SF-36) and disease-specific surveys (e.g., the CFQ-R for cystic fibrosis) are used.

Block 6: Calculations & Advanced Topics

Cost-Effectiveness Analysis

Organizations like the Institute for Clinical and Economic Review (ICER) evaluate whether the high price of an orphan drug is justified by its clinical benefit, often using metrics like the cost per Quality-Adjusted Life Year (QALY) gained.

Value-Based & Annuity Payment Models

To manage the extreme cost of one-time therapies, novel payment models are emerging, such as outcomes-based agreements (where payment is tied to patient success) or paying for the drug over several years, like an annuity.

  • Pharmacist's Role: While genetic counselors are the primary experts, the CRDP must have a foundational understanding of genetic test reports to verify patient eligibility for genotype-specific therapies.
  • Strategic Decision: Determining the most clinically appropriate and cost-effective setting to administer a high-cost drug (e.g., hospital outpatient, physician's office, or home infusion) is a key role that requires collaboration between the pharmacy, provider, and payer.
  • Resource Allocation: The tension between providing extremely expensive drugs for a few patients versus providing broader public health services for many.
  • Informed Consent: Ensuring patients truly comprehend the novel nature of the treatment, the potential for life-threatening short-term risks, and the known and unknown long-term risks is a major ethical challenge.
  • Be a Compassionate Expert: The role requires both deep clinical and operational expertise and a high degree of empathy for the immense challenges patients and families face.
  • Master of Logistics: A successful CRDP is a master of project management, coordinating dozens of moving parts across multiple stakeholders to ensure seamless patient care.
  • Embrace the "N-of-1" Mindset: In rare disease, every patient is unique. The pharmacist must be adept at individualizing care and making decisions based on limited data and the specific patient in front of them.
  • Resilience is Key: Navigating insurance denials, logistical hurdles, and the emotional weight of caring for seriously ill patients requires a high level of professional resilience and perseverance.
  • You Are a Beacon of Hope: For many patients who have been told there are no options, the rare disease pharmacist is a critical guide and a source of hope on their treatment journey.
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