09 Spring Career Fair

The embodiment of deepening economic downturn is packed career fair. Last Wednesday, I headed to Homewood Campus at Baltimore to participate in my first job fair in the U.S.

I got there at 1 P.M., which normally is see-you time in a career fair. There was still many students walking arround in the Rec. Center for their job hunting. Not to my surprise, positions of many big companies are fopen or U.S. citizen or Green Card holder only. Even internship application is not easy. Take Accenture as an example, they do not recurit foreign students in their intern program.

What I did on that day is submit my CV to FDA for summer intern application. But, they did not come back to me until now... I may go HW again on March 3, to meet FDA representative and follow up my intern opportunity.

It is a experience anyway. Nothing to win or loose.

02/04/09 BLA - Dyax Corp.-ecallantide for the treatment of acute attacks of hereditary angioedema

Disease:
Hereditary Angioedema (HAE) is a rare disease. Approximately 10,000 individual suffers. Less than 50% properly diagnosed. The major symptom is edema (swelling) in various body parts including hands, face, feet and airway. It is a potentially life-threatening disease when HAE attack laryngeal. The reason of HAE is deficiency in C1 esterase inhibitor activity, which are believed to block Kallikrein (血管舒缓素) Synthesis and decrease Bradykinin (血管舒缓激肽).

Medicine:
FDA approved several medicines for short and long term prophylaxis like Androgens, but no for acute attack. (Androgens have SAEs).
Dyax use recombinant technology to produce a protein, called Ecallantide, to specifically inhabit Kallikrein and suppress Bradykinin. Then physiological symptom, Edema, disappear. According to stability study, Ecallantide injection can be stored at 2-8 C for two years and at room temperature for 2 weeks.

Clinical studies:
Due to it is a rare disease, 219 HAE patients (4% of patients seeking treatment) were enrolled in the studies. The 219 HAE patients received 609 doses totally.

Design:
Phase 1 and Phase 2:
4 studies in Healthy subjects: DB, placebo-controlled, IV, PK, dose escalation
EDEMA0 / EDEMA1: single IV dose, 1 open-label, 1 placebo-controlled
EDEMA 2: Multi-dose, IV or Sbq, OL.
Phase 3:
EDEMA 3: DB, single dose, 30mg subq, placebo-controlled
EDEMA 3: RD, 30mg subq, open label
EDEMA 4: DB, Single-dose, 30mg subq, placebo-controlled
Ongoing continuation study: RD, OL

Efficacy measurement tool: Patient-Reported Outcome (PRO) assessment
Refer to FDA guideline: Patient-reported outcome measures.
Tool 1:Mean Symptom Complex Severity (MSCS): Point-in-time assessment of symptom severity
Tool 2:Treatment Outcome Score (TOS): Assessment of response to treatment.

Safety: Ecallantide is a foreign protein. So, the main concern is anaphylaxis and hyperandsensitivity caused by ecallantide.
Adverse events/physical exams/vital signs/routine clinical lab test and urinanalysis/ECG/Serial antibody testing

Sponsor conclusion:
No exception, the data sponsor present are “substantial” and “convincing” evidence of studies.

FDA conclusion:
FDA point out several issues about studies:
1) In EDEMA3: Dose administration error.
2) In EDEMA4: sample size increased from 52 to 96. It leads to the decrease of P value.
3) Pediatric data is limited.
Efficacy:
- EDEMA3 results not statistically significant by the pre-specified analysis
- EDEMA4 results of questionable robustness
- Pediatric data is limited
Safety
- Significant risk of anaphylaxis
- Limited data in pediatric patients.

Advisory committee
Voting (5 questions)
Question 4: Do the safety and efficacy data provide substantial and convincing evidence to support the approval of ecallantide for the treatment of acute attacks of hereditary angioedema?
Yes: 6 No: 5 Abstain: 2

Comments:
data is inadequate.
Rechallenge study is crude. It put patients in extremely dangerous situation.
If approved, post-marketing study is necessary.

My comments:
Apparently, the clinical data is inadequate, especially, pediatric data. In addition, sponsor changed the sample size of EDEMA 4 (add 44 patients) in order to get statistically significant results. Considering it is an orphan drug, advisory committee member may lower their standard of judgment.

First exprience of meeting of FDA Adviosry Committee

I began to plan my 1st meeting of FDA Advisory Committee participation since last september, when my first semester started. The convience of regulatory meeting participation is my preliminary reason for choosing Johns Hopkins.

The meeting was hold at Hilton hotel, Gaithersburg. The meeting location is close to where I live -- Approximately, 15 minutes by bus. But, it takes me 20 minutes to walk to nearest No. 54 bus stop...

I arrived at Hilton several minutes later than I thought becasue the bus is later against schedule. Sign in, meeting material pick up and sneak into the salon. I felt awkward when I found that most of participants dressed formally. The cold weather and long-distance walking discouraged me from wearing suit and leather shoes.

The meeting was open to public from beginning to end. The arrangement was very good. Agenda, sponsor/FDA presentation slides, and other meeting handouts were free and easily accessible.

The whole meeting is not boring as I thought. I did not take out and read my Biostatistics textbook, which was going to kill extra time. Although language is still an obstacle, I could understand what they talked about. It would be helpful, if I reviewed the meeting briefing package before meeting.

Generally speaking, the meeting worth participation. I will detail the meeting later.

Unknown name plant

I don't exactly have a green thumb.

(To be continued...when I know the name of my plant...)